Methods and compositions for treating hyperhidrosis

ABSTRACT

Aspects of the disclosure include methods for treating hyperhidrosis in a subject with a composition including a muscarinic antagonist and a muscarinic agonist. In practicing methods according to certain embodiments, a therapeutically effective amount of a composition including a muscarinic antagonist or a pharmaceutically acceptable salt thereof and a muscarinic agonist or a pharmaceutically acceptable salt thereof is administered to a subject and is sufficient to reduce hyperhidrosis in the subject and to reduce a dry mouth side effect of the muscarinic antagonist. Compositions for practicing the subject methods are also described as well as dose units containing one or more of the subject compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/US2016/14150, filed Jan. 20, 2016, which application isincorporated herein by reference in its entirety.

A portion of the disclosure of this patent document contains materialwhich is subject to (copyright or mask work) protection. The (copyrightor mask work) owner has no objection to the facsimile reproduction byanyone of the patent document or the patent disclosure, as it appears inthe Patent and Trademark Office patent file or records, but otherwisereserves all (copyright or mask work) rights whatsoever.

INTRODUCTION

Sweat is an essential physiological function to human survival andserves as a body's coolant, protecting it from overheating. Eccrineglands secrete an odorless, clear fluid that helps the body to controlits temperature by promoting heat loss through evaporation. Apocrineglands produce a thicker fluid which is often found in the armpits andnear the genitals. Both the eccrine and apocrine sweat glands areactivated by nerves.

Hyperhidrosis is a disorder characterized by an abnormal amount ofsweating in excess of that required for regulation of body temperature.Hyperhidrosis can be either generalized or localized to specific partsof the body, including the hands, feet, armpits and genital region. Itis estimated that 2-3% of Americans suffer from excessive sweating ofthe underarms (axillary hyperhidrosis), of the palms (palmarhyperhidrosis) or the soles of the feet (plantar hyperhidrosis).Prolonged hyperhidrosis can result in cold and clammy hands, dehydrationas well as skin infections. However, most commonly subjects sufferingfrom hyperhidrosis experience a significant quality of life burden froma psychological, emotional and social perspective, often modifying theirlifestyles to accommodate the condition, which can lead to a disablingprofessional, academic and social life.

SUMMARY

Aspects of the disclosure include methods for treating hyperhidrosis ina subject with a composition including a muscarinic antagonist and amuscarinic agonist. In practicing methods according to certainembodiments, a therapeutically effective amount of a composition havinga muscarinic antagonist, or a pharmaceutically acceptable salt thereof,and a muscarinic agonist, or a pharmaceutically acceptable salt thereof,is administered to a subject and is sufficient to reduce hyperhidrosisin the subject and to reduce a dry mouth side effect of the muscarinicantagonist. Compositions for practicing the subject methods are alsodescribed as well as dose units containing one or more of the subjectcompositions.

Certain muscarinic agonists, in particular pilocarpine, are known tocause an increase in sweating. See, e.g., Salagen® (pilocarpine HCl)product insert (©2003 MGI Pharma, Inc.). Accordingly, it was unexpectedthat the administration of a composition including both a muscarinicantagonist and a muscarinic agonist, such as pilocarpine, according tothe subject methods, would effectively treat hyperhidrosis whilereducing a dry mouth side effect of the muscarinic antagonist.Surprisingly, as demonstrated herein, it was found that the muscarinicagonist neither diminished the efficacy of the muscarinic antagonist intreating hyperhidrosis nor caused an increase in sweating in thesubjects as is generally expected with the administration of amuscarinic agonist such as pilocarpine.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a process for manufacturing pilocarpine beadsaccording to one embodiment.

FIG. 2 depicts the dissolution profile of delayed onset immediaterelease pilocarpine beads according to one embodiment.

FIG. 3 illustrates a process for manufacturing an oxybutynin granulateaccording to one embodiment.

FIG. 4 depicts the dissolution profile of an immediate releaseoxybutynin granulate in a gelatin capsule according to one embodiment.

FIG. 5 illustrates a scheme for a clinical study design foradministering to a group of subjects a composition of oxybutynin andpilocarpine according to one embodiment.

FIG. 6 depicts the axillary Hyperhidrosis Visual Quantification Scale(HHVQSa) used to assess treatment according to one embodiment.

FIG. 7 depicts the palmar Hyperhidrosis Visual Quantification Scale(HHVQSp) used to assess treatment according to one embodiment.

FIG. 8 depicts the Hyperhidrosis Visual Analog Scale (HHVAS) used toassess sweating according to one embodiment.

FIG. 9 depicts the Dry Mouth Visual Analog Scale used to assess drymouth caused by administration of oxybutynin according to oneembodiment.

FIG. 10 depicts the improvement in quality of life as measured by amodified Dermatology Life Quality Index according to one embodiment.

DETAILED DESCRIPTION

Aspects of the disclosure include methods and compositions for treatinghyperhidrosis in a subject with a composition including a muscarinicantagonist and a muscarinic agonist. In practicing methods according tocertain embodiments, a therapeutically effective amount of a compositionhaving a muscarinic antagonist or a pharmaceutically acceptable saltthereof and a muscarinic agonist or a pharmaceutically acceptable saltthereof is administered to a subject and is sufficient to reducehyperhidrosis in the subject and to reduce a dry mouth side effect ofthe muscarinic antagonist in the subject.

Before the present disclosure is described in greater detail, it is tobe understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating nonrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number. In someembodiments, the term “about”, when used to modify a value, encompassesa value that is within 15%, e.g., within 10%, e.g., within 5%, of thevalue modified by the term “about”.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure,representative illustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present disclosure is not entitled to antedate suchpublication by virtue of prior disclosure. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any recited element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

In further describing various embodiments of the disclosure, methods fortreating hyperhidrosis by administering a therapeutically effectiveamount of a composition including a muscarinic antagonist or apharmaceutically acceptable salt thereof and a muscarinic agonist or apharmaceutically acceptable salt thereof are reviewed first in greaterdetail. Next, compositions and dose units for practicing methods of thesubject disclosure are described.

Methods for Treating Hyperhidrosis

As summarized above, aspects of the disclosure include methods fortreating hyperhidrosis by administering to a subject a compositionhaving a therapeutically effective amount of a composition including amuscarinic antagonist or a pharmaceutically acceptable salt thereof anda muscarinic agonist or a pharmaceutically acceptable salt thereof. Inembodiments of the present disclosure, the subject methods may beemployed in the treatment of primary (focal) hyperhidrosis or secondaryhyperhidrosis. In some embodiments, the subject methods include treatinglocalized hyperhidrosis, such as axillary hyperhidrosis, palmarhyperhidrosis, plantar hyperhidrosis, or craniofacial hyperhidrosis. Insome embodiments, the subject methods include treating generalizedhyperhidrosis or compensatory sweating post-surgery. By treatment ismeant that at least an amelioration of the symptoms or characteristicsassociated with hyperhidrosis afflicting the subject is achieved, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude, such as a reduction in excessive sweating experiencedby the subject. As such, treatment also includes situations where thepathological condition, or at least symptoms or characteristicsassociated therewith, are completely inhibited, e.g., prevented fromhappening, or stopped, e.g., terminated, such that the subject no longersuffers from the condition, or at least the symptoms that characterizethe condition. The phrase “treating hyperhidrosis” is used herein in itsconventional sense to refer to reducing, ameliorating or altogethereliminating excessive sweating as experienced by the subject. In certainembodiments, treating hyperhidrosis includes reducing excessive sweatingexperienced by the subject, such as where excessive sweating by thesubject is reduced by about 5% or more as reported by the subject or asdetermined by gravimetric assessments, on the Hyperhidrosis DiseaseSeverity Scale (HDSS), by measurement by transdermal epidural watervapor loss (e.g., Vapometer, Delfin Technologies, Kuopio Finland), onthe Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa orHHVQSp), on the Hyperhidrosis Visual Analog Scale (HHVAS) or anycombination thereof. For example, the subject methods may includetreating hyperhidrosis, wherein the treatment is sufficient to reduceexcessive sweating by 10% or more, such as by about 25% or more, such asby about 50% or more, such as by about 75% or more, such as by about 90%or more and including reducing excessive sweating experienced by thesubject by about 99% or more as reported by the subject or as determinedby gravimetric assessments, on the Hyperhidrosis Disease Severity Scale(HDSS), by measurement by transdermal epidural water vapor loss (e.g.,Vapometer, Delfin Technologies, Kuopio Finland), on the HyperhidrosisVisual Quantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on theHyperhidrosis Visual Analog Scale (HHVAS) or any combination thereof. Inother embodiments, treating hyperhidrosis includes altogethereliminating excessive sweating experienced by the subject.

In some embodiments, the treatment is sufficient to reduce excessivesweating by about 5% to about 25%, about 25% to about 50%, about 75% toabout 90%, or by about 90% to about 99%, as reported by the subject oras determined by gravimetric assessments, on the Hyperhidrosis DiseaseSeverity Scale (HDSS), by measurement by transdermal epidural watervapor loss (e.g., Vapometer, Delfin Technologies, Kuopio Finland), onthe Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa orHHVQSp), on the Hyperhidrosis Visual Analog Scale (HHVAS) or anycombination thereof.

As described in greater detail below, the subject compositions includean amount of a muscarinic antagonist or a pharmaceutically acceptablesalt thereof and an amount of a muscarinic agonist or a pharmaceuticallyacceptable salt thereof. According to certain aspects of the presentdisclosure, the muscarinic agonist is present in the composition in anamount sufficient to reduce one or more side effects caused by themuscarinic antagonist, such as dry mouth. In certain instances, themuscarinic antagonist is oxybutynin or a pharmaceutically acceptablesalt thereof and the muscarinic agonist is pilocarpine or apharmaceutically acceptable salt thereof and the pilocarpine or apharmaceutically acceptable salt thereof is present in the compositionin an amount sufficient to reduce one or more side effects caused by theadministration of oxybutynin or a pharmaceutically acceptable saltthereof. In certain embodiments, pilocarpine or a pharmaceuticallyacceptable salt thereof is present in an amount sufficient to reduce drymouth caused by oxybutynin or a pharmaceutically acceptable saltthereof. The muscarinic agonist or a pharmaceutically acceptable saltthereof (e.g., pilocarpine or pilocarpine HCl) may be administered withthe muscarinic antagonist or a pharmaceutically acceptable salt thereof(e.g., oxybutynin or oxybutynin HCl) to the subject in an amountsufficient to alleviate dry mouth by about 25% or more, such as by about50% or more, such as by about 75% or more, such as by about 90% or more,such as by about 95% or more and including by about 99% or more asreported by the subject or as assessed by the Dry Mouth Visual AnalogScale (DMVAS), by measuring salivary flow, by a Dry MouthSeverity/Incidence Questionnaire, e.g., as described herein, or acombination thereof.

In some embodiments, the muscarinic agonist or a pharmaceuticallyacceptable salt thereof (e.g., pilocarpine or pilocarpine HCl) may beadministered with the muscarinic antagonist or a pharmaceuticallyacceptable salt thereof (e.g., oxybutynin or oxybutynin HCl) to thesubject in an amount sufficient to reduce the severity of dry mouth byabout 25% to about 50%, by about 50% to about 75%, by about 75% to about90%, from about 90% to about 95%, or from about 95% to about 99% or moreas reported by the subject or as assessed by the Dry Mouth Visual AnalogScale (DMVAS), by measuring salivary flow, by a Dry MouthSeverity/Incidence Questionnaire, e.g., as described herein, or acombination thereof.

In certain embodiments the muscarinic agonist or a pharmaceuticallyacceptable salt thereof (e.g., pilocarpine or pilocarpine HCl) isadministered with the muscarinic antagonist or a pharmaceuticallyacceptable salt thereof (e.g., oxybutynin or oxybutynin HCl) to thesubject in an amount sufficient to completely alleviate dry mouth causedby the muscarinic antagonist as reported by the subject or as assessedby the Dry Mouth Visual Analog Scale (DMVAS), by measuring salivaryflow, by a Dry Mouth Severity/Incidence Questionnaire, e.g., asdescribed herein, or a combination thereof.

In some embodiments, the muscarinic agonist or a pharmaceuticallyacceptable salt thereof (e.g., pilocarpine or pilocarpine HCl) may beadministered with the muscarinic antagonist or a pharmaceuticallyacceptable salt thereof (e.g. oxybutynin or oxybutynin HCl) to thesubject in an amount sufficient to reduce the number of incidences ofmoderate to severe dry mouth by about 25% to about 50%, by about 50% toabout 75%, by about 75% to about 90%, from about 90% to about 95%, orfrom about 95% to about 99% or more as reported by the subject or asassessed by the Dry Mouth Visual Analog Scale (DMVAS), by measuringsalivary flow, by a Dry Mouth Severity/Incidence Questionnaire, e.g., asdescribed herein, or a combination thereof.

In certain embodiments the muscarinic agonist or a pharmaceuticallyacceptable salt thereof (e.g., pilocarpine or pilocarpine HCl) isadministered with the muscarinic antagonist or a pharmaceuticallyacceptable salt thereof (e.g., oxybutynin or oxybutynin HCl) to thesubject in an amount sufficient to completely eliminate the number ofincidences of moderate or severe dry mouth caused by the muscarinicantagonist as reported by the subject or as assessed by the Dry MouthVisual Analog Scale (DMVAS), by measuring salivary flow, by a Dry MouthSeverity/Incidence Questionnaire, e.g., as described herein, or acombination thereof.

Certain muscarinic agonists, in particular pilocarpine, are known tocause an increase in sweating, for example as shown in Jacobs: AMulticenter Maintenance Study of Oral Pilocarpine Tablets forRadiation-Induced Xerostomia, Oncology, 1996; 10 {Suppl}:16-20; andCheshire and Fealey: Drug-Induced Hyperhidrosis and HypohidrosisIncidence, Prevention and Management, Drug Safety, 2008; 31(2):109-126;and in the Salagen® (pilocarpine HCl) product insert (© 2003 MGI Pharma,Inc.). In view of such teachings, it was unexpectedly found thatadministering a muscarinic agonist in combination with a muscarinicantagonist to a subject did not result in an increase in sweating in thesubjects and did not significantly diminish the efficacy of themuscarinic antagonist in the context of hyperhidrosis treatment. Asdescribed in greater detail in the experimental section below, whenadministering a composition including a muscarinic antagonist and amuscarinic agonist in accordance with the present disclosure, thecomposition is effective at treating hyperhidrosis by reducing excessivesweating experienced by the subject such as reported by the subject oras measured by gravimetric assessments, on the Hyperhidrosis DiseaseSeverity Scale (HDSS), by measurement by transdermal epidural watervapor loss (e.g., Vapometer, Delfin Technologies, Kuopio Finland), onthe Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa orHHVQSp), on the Hyperhidrosis Visual Analog Scale (HHVAS) or anycombination thereof.

In certain embodiments, administering a composition including amuscarinic antagonist or a pharmaceutically acceptable salt thereof anda muscarinic agonist or a pharmaceutically acceptable salt thereof inaccordance with the present disclosure is at least as effective attreating hyperhidrosis by reducing excessive sweating by the subject asadministering the muscarinic antagonist or a pharmaceutically acceptablesalt thereof alone. By “at least as effective” in this context is meantthat the composition containing a combination of muscarinic antagonist,or a pharmaceutically acceptable salt thereof, and a muscarinic agonistor a pharmaceutically acceptable salt thereof is at least 70% aseffective at reducing hyperhidrosis in the subject as when themuscarinic antagonist or pharmaceutically acceptable salt thereof isadministered alone, as reported by the subject or as measured bygravimetric assessments, on the Hyperhidrosis Disease Severity Scale(HDSS), by measurement by transdermal epidural water vapor loss (e.g.,Vapometer, Delfin Technologies, Kuopio Finland), on the HyperhidrosisVisual Quantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on theHyperhidrosis Visual Analog Scale (HHVAS) or any combination thereof,such as at least 85%, such as at least 90%, such as at least 95%, suchas at least 97% and including at least 99% as effective at reducinghyperhidrosis in the subject as when a muscarinic antagonist or apharmaceutically acceptable salt is administered alone.

In certain embodiments, the subject compositions of the muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof are equallyeffective at reducing excessive sweating experienced by the subject asadministration of the muscarinic antagonist or a pharmaceuticallyacceptable salt thereof alone, as reported by the subject or as measuredby gravimetric assessments, on the Hyperhidrosis Disease Severity Scale(HDSS), by measurement by transdermal epidural water vapor loss (e.g.,Vapometer, Delfin Technologies, Kuopio Finland), on the HyperhidrosisVisual Quantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on theHyperhidrosis Visual Analog Scale (HHVAS) or any combination thereof.

In certain embodiments, administering a muscarinic agonist orpharmaceutically acceptable salt thereof in combination with amuscarinic antagonist or pharmaceutically acceptable salt thereof inaccordance with the present disclosure does not substantially reduce theefficacy of the muscarinic antagonist or pharmaceutically acceptablesalt thereof in treating hyperhidrosis relative to administration of themuscarinic antagonist or a pharmaceutically acceptable salt thereofalone. For example, in embodiments, the muscarinic agonist orpharmaceutically acceptable salt thereof reduces the efficacy of themuscarinic antagonist or pharmaceutically acceptable salt thereof intreating hyperhidrosis by 30% or less as measured by gravimetricassessments, on the Hyperhidrosis Disease Severity Scale (HDSS), bymeasurement by transdermal epidural water vapor loss (e.g., Vapometer,Delfin Technologies, Kuopio Finland), on the Hyperhidrosis VisualQuantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on theHyperhidrosis Visual Analog Scale (HHVAS), such as by 25% or less, suchas by 20% or less, such as by 15% or less, such as by 10% or less, suchas by 5% or less, such as by 2% or less and including by 1% or less asmeasured by gravimetric assessments, on the Hyperhidrosis DiseaseSeverity Scale (HDSS), by measurement by transdermal epidural watervapor loss (e.g., Vapometer, Delfin Technologies, Kuopio Finland), onthe Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa orHHVQSp), on the Hyperhidrosis Visual Analog Scale (HHVAS). In certainembodiments, the muscarinic agonist or pharmaceutically acceptable saltthereof does not reduce the efficacy of the muscarinic antagonist orpharmaceutically acceptable salt thereof in treating hyperhidrosis atall (i.e., by 0%) as measured by gravimetric assessments, on theHyperhidrosis Disease Severity Scale (HDSS), by measurement bytransdermal epidural water vapor loss (e.g., Vapometer, DelfinTechnologies, Kuopio Finland), on the Hyperhidrosis VisualQuantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on theHyperhidrosis Visual Analog Scale (HHVAS).

In embodiments of the present disclosure, methods for treatinghyperhidrosis in a subject are provided. By “subject” is meant theperson or organism administered the composition including atherapeutically effective amount of a composition including a muscarinicantagonist or a pharmaceutically acceptable salt thereof and amuscarinic agonist or a pharmaceutically acceptable salt thereof. Assuch, subjects of the disclosure may include but are not limited tomammals, e.g., humans and other primates, such as chimpanzees and otherapes and monkey species; and the like, where in certain embodiments thesubject are humans.

In embodiments of the present disclosure, methods include administeringto a subject a therapeutically effective amount of a compositionincluding a muscarinic antagonist or a pharmaceutically acceptable saltthereof and a muscarinic agonist or a pharmaceutically acceptable saltthereof. The muscarinic antagonist may be any type of anticholinergicagent that blocks the activity of the muscarinic acetylcholine receptor,such as blockers of the M₁, M₂, M₃, M₄ or M₅ muscarinic receptorisoforms. In some embodiments, muscarinic antagonists suitable for usein the subject methods is one or more of oxybutynin, tolterodine,5-hydroxymethyl tolterodine, fesoterodine, solifenacin, darifenaccin,tropsium, imidafenacin, propiverine or dicyclomine or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the muscarinicantagonist is oxybutynin (4-Diethylaminobut-2-ynyl2-cyclohexyl-2-hydroxy-2-phenylethanoate) or a pharmaceuticallyacceptable salt thereof.

Depending on the physiology of the subject, the amount of muscarinicantagonist or pharmaceutically acceptable salt thereof administered tothe subject may vary, such as 0.5 mg or more, such as 1.5 mg or more,such as 2.5 mg or more, such as 3.0 mg or more, such as 3.5 mg or more,such as 4.0 mg or more, such as 4.5 mg or more, such as 5.0 mg or more,such as 5.5 mg or more, such as 6.0 mg or more, such as 6.5 mg or more,such as 7.0 mg or more, such as 7.5 mg or more, such as 8.0 mg or more,such as 8.5 mg or more, such as 9.0 mg or more, such as 9.5 mg or moreand including 10 mg or more. For example, the amount of muscarinicantagonist administered to the subject may range from 0.5 mg to 50 mg,such as from 1 mg to 40 mg, such as from 2 mg to 40 mg, such as from 3mg to 30 mg, such as from 4 mg to 25 mg, such as from 5 mg to 20 mg andincluding from 5 mg to 10 mg, for example 7.5 mg. In certainembodiments, the amount of muscarinic antagonist or pharmaceuticallyacceptable salt thereof administered to the subject is 7.5 mg. In otherembodiments, the amount of muscarinic antagonist or pharmaceuticallyacceptable salt thereof administered to the subject is 5.0 mg.

In certain embodiments, the muscarinic antagonist is oxybutynin orpharmaceutically acceptable salt thereof and the amount of oxybutynin orpharmaceutically acceptable salt thereof administered to the subject is0.5 mg or more, such as 1.5 mg or more, such as 2.5 mg or more, such as3.0 mg or more, such as 3.5 mg or more, such as 4.0 mg or more, such as4.5 mg or more, such as 5.0 mg or more, such as 5.5 mg or more, such as6.0 mg or more, such as 6.5 mg or more, such as 7.0 mg or more, such as7.5 mg or more, such as 8.0 mg or more, such as 8.5 mg or more, such as9.0 mg or more, such as 9.5 mg or more and including 10 mg or more. Forexample, the amount of oxybutynin or pharmaceutically acceptable saltthereof administered to the subject may range from 0.5 mg to 50 mg, suchas from 1 mg to 45 mg, such as from 2 mg to 40 mg, such as from 3 mg to30 mg, such as from 4 mg to 25 mg, such as from 5 mg to 20 mg andincluding from 5 mg to 10 mg, for example 7.5 mg. In certainembodiments, the amount of oxybutynin or pharmaceutically acceptablesalt thereof administered to the subject is 7.5 mg. In otherembodiments, the amount of oxybutynin or pharmaceutically acceptablesalt thereof administered to the subject is 5.0 mg.

In embodiments of the present disclosure, the muscarinic agonist may beany type of agent that activates the activity of the muscarinicacetylcholine receptor, such as activators of the M₁, M₂, M₃, M₄ or M₅muscarinic receptor isoforms. In some embodiments, muscarinic agonistssuitable for use in the subject methods is one or more of pilocarpine,choline, acetylcholine, carbachol, methacholine, bethanechol, muscarine,nicotine, or oxotremorine. In certain embodiments, the muscarinicagonist is pilocarpine((3S,4R)-3-Ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)dihydrofuran-2(3H)-one)or a pharmaceutically acceptable salt thereof.

Depending on the physiology of the subject and the amount of muscarinicagonist administered, the amount of muscarinic agonist orpharmaceutically acceptable salt thereof administered to the subject mayvary, such as 0.5 mg or more, such as 1.5 mg or more, such as 2.5 mg ormore, such as 3.0 mg or more, such as 3.5 mg or more, such as 4.0 mg ormore, such as 4.5 mg or more, such as 5.0 mg or more, such as 5.5 mg ormore, such as 6.0 mg or more, such as 6.5 mg or more, such as 7.0 mg ormore, such as 7.5 mg or more, such as 8.0 mg or more, such as 8.5 mg ormore, such as 9.0 mg or more, such as 9.5 mg or more and including 10 mgor more. For example, the amount of muscarinic agonist administered tothe subject may range from 0.5 mg to 50 mg, such as from 1 mg to 45 mg,such as from 2 mg to 40 mg, such as from 3 mg to 30 mg, such as from 4mg to 25 mg, such as from 5 mg to 20 mg and including from 3 mg to 10mg, for example 7.5 mg. In certain embodiments, the amount of muscarinicagonist or pharmaceutically acceptable salt thereof administered to thesubject is 7.5 mg. In other embodiments, the amount of muscarinicagonist or pharmaceutically acceptable salt thereof administered to thesubject is 5.0 mg.

In certain embodiments, the muscarinic agonist is pilocarpine or apharmaceutically acceptable salt thereof and the amount of pilocarpineor pharmaceutically acceptable salt thereof administered to the subjectis 0.5 mg or more, such as 1.5 mg or more, such as 2.5 mg or more, suchas 3.0 mg or more, such as 3.5 mg or more, such as 4.0 mg or more, suchas 4.5 mg or more, such as 5.0 mg or more, such as 5.5 mg or more, suchas 6.0 mg or more, such as 6.5 mg or more, such as 7.0 mg or more, suchas 7.5 mg or more, such as 8.0 mg or more, such as 8.5 mg or more, suchas 9.0 mg or more, such as 9.5 mg or more and including 10 mg or more.For example, the amount of pilocarpine or pharmaceutically acceptablesalt thereof administered to the subject may range from 0.5 mg to 50 mg,such as from 1 mg to 45 mg, such as from 2 mg to 40 mg, such as from 3mg to 30 mg, such as from 4 mg to 25 mg, such as from 5 mg to 20 mg andincluding from 3 mg to 10 mg, for instance 7.5 mg. In certainembodiments, the amount of pilocarpine or pharmaceutically acceptablesalt thereof administered to the subject is 7.5 mg. In otherembodiments, the amount of pilocarpine or pharmaceutically acceptablesalt thereof administered to the subject is 5.0 mg.

The mass ratio of the muscarinic antagonist or pharmaceuticallyacceptable salt thereof and the muscarinic agonist or pharmaceuticallyacceptable salt thereof administered to the subject may vary, rangingbetween 1:1 and 1:2.5; 1:2.5 and 1:5; 1:5 and 1:10; 1:10 and 1:25; 1:25and 1:50; 1:50 and 1:100, ora range thereof. For example, where themuscarinic antagonist is oxybutynin or a pharmaceutically acceptablesalt thereof and the muscarinic agonist is pilocarpine or apharmaceutically acceptable salt thereof, the mass ratio of theoxybutynin and pilocarpine administered to the subject may range from1:1 to 1:10; or from 1:5 to 1:25; or from 1:10 to 1:50; or from 1:25 to1:100.

In some embodiments, the mass ratio of the muscarinic agonist orpharmaceutically acceptable salt thereof and the muscarinic antagonistor pharmaceutically acceptable salt thereof administered to the subjectranges between 1:1 and 1:2.5; 1:2.5 and 1:5; 1:5 and 1:10; 1:10 and1:25; 1:25 and 1:50; 1:50 and 1:100, or a range thereof. For example,where the muscarinic antagonist is oxybutynin or a pharmaceuticallyacceptable salt thereof and the muscarinic agonist is pilocarpine or apharmaceutically acceptable salt thereof, the mass ratio of thepilocarpine and oxybutynin administered to the subject may range from1:1 to 1:10; or from 1:5 to 1:25; or from 1:10 to 1:50 or from 1:25 to1:100.

Accordingly, the dosage of muscarinic antagonist or pharmaceuticallyacceptable salt thereof and muscarinic agonist or pharmaceuticallyacceptable salt thereof may vary, ranging from about 0.1 mg/kg to 25mg/kg per day, such as from 0.1 mg/kg to 20 mg/kg per day, such as 0.1mg/kg to 18 mg/kg per day, such as 0.1 mg/kg to 15 mg/kg per day, suchas 0.1 mg/kg to 10 mg/kg per day, and including 0.1 mg/kg to 5 mg/kg perday. In other embodiments, the dosage may range from 0.1 to 6.5 mg/kgfour times per day (QID), such as 0.1 to 5 mg/kg QID, such as 0.1 mg/kgto 4 mg/kg QID. In other embodiments, the oral dosage may range from0.01 mg/kg to 8.5 mg/kg three times per day (TID), such as 0.1 mg/kg to6 mg/kg TID, such as 0.1 mg/kg to 5 mg/kg TID, and including as 0.1mg/kg to 4 mg/kg TID. In yet other embodiments, the oral dosage mayrange from 0.1 mg/kg to 13 mg/kg two times per day (BID), such as 0.1mg/kg to 12 mg/kg BID, such as 5 mg/kg to 10 mg/kg BID, including 0.1mg/kg to 8 mg/kg BID.

In embodiments, the total daily amount of muscarinic antagonist orpharmaceutically acceptable salt thereof administered to the subject is2.5 mg or more, such as 5 mg or more, such as 7.5 mg or more, such as 10mg or more, such as 15 mg or more, such as 20 mg or more, such as 25 mgor more and including 30 mg or more. For example, the total daily amountof muscarinic antagonist administered to the subject may range from 0.5mg to 50 mg, such as from 1 mg to 40 mg, such as from 2 mg to 40 mg,such as from 3 mg to 30 mg, such as from 4 mg to 25 mg, such as from 5mg to 20 mg and including from 5 mg to 10 mg. In certain instances, themuscarinic antagonist is oxybutynin or a pharmaceutically acceptablesalt thereof and the total daily amount of oxybutynin orpharmaceutically acceptable salt thereof administered to the subject is2.5 mg or more, such as 5 mg or more, such as 7.5 mg or more, such as 10mg or more, such as 15 mg or more, such as 20 mg or more, such as 25 mgor more and including 30 mg or more, such as ranging from 0.5 mg to 50mg, such as from 1 mg to 40 mg, such as from 2 mg to 40 mg, such as from3 mg to 30 mg, such as from 4 mg to 25 mg, such as from 5 mg to 20 mgand including from 5 mg to 10 mg.

In embodiments, the total daily amount of muscarinic agonist orpharmaceutically acceptable salt thereof administered to the subject is2.5 mg or more, such as 5 mg or more, such as 7.5 mg or more, such as 10mg or more, such as 15 mg or more, such as 20 mg or more, such as 25 mgor more and including 30 mg or more. For example, the total daily amountof muscarinic agonist administered to the subject may range from 0.5 mgto 50 mg, such as from 1 mg to 40 mg, such as from 2 mg to 40 mg, suchas from 3 mg to 30 mg, such as from 4 mg to 25 mg, such as from 5 mg to20 mg and including from 5 mg to 10 mg. In certain instances, themuscarinic agonist is pilocarpine or a pharmaceutically acceptable saltthereof and the total daily amount of pilocarpine or pharmaceuticallyacceptable salt thereof administered to the subject is 2.5 mg or more,such as 5 mg or more, such as 7.5 mg or more, such as 10 mg or more,such as 15 mg or more, such as 20 mg or more, such as 25 mg or more andincluding 30 mg or more, such as ranging from 0.5 mg to 50 mg, such asfrom 1 mg to 40 mg, such as from 2 mg to 40 mg, such as from 3 mg to 30mg, such as from 4 mg to 25 mg, such as from 5 mg to 20 mg and includingfrom 5 mg to 10 mg.

The amount of compound administered will depend on the physiology of thesubject, the absorptivity of the muscarinic antagonist and muscarinicagonist by the subject, as well as the magnitude of therapeutic effectdesired. Dosing schedules may include, but are not limited toadministration five times per day, four times per day, three times perday, twice per day, once per day, three times per week, twice per week,once per week, twice per month, once per month, and any combinationthereof.

In practicing the subject methods, compositions including a muscarinicantagonist or a pharmaceutically acceptable salt thereof (e.g.,oxybutynin or a pharmaceutically acceptable salt thereof) and amuscarinic agonist or a pharmaceutically acceptable salt thereof (e.g.,pilocarpine or a pharmaceutically acceptable salt thereof) may beadministered to treat the subject for hyperhidrosis for a duration thatvaries, depending on the type of hyperhidrosis (e.g., generalized,palmar, plantar, axillary, craniofacial, compensatory sweatingpost-surgery, etc.) and severity of the condition, as determined by aqualified health care professional. For example, the subjectcompositions may be administered to treat hyperhidrosis for a period of1 week or longer, such as 3 weeks or longer, such as 1 month or longer,such as 3 months or longer, such as 6 months or longer, such as 9 monthsor longer, such as 1 year or longer and including 5 years or longer.

In certain embodiments, compositions of the disclosure can be orallyadministered prior to, concurrent with, or subsequent to other agentsfor treating related or unrelated conditions. If provided at the sametime as other agents, compositions of the invention can be provided inthe same or in a different composition. For example, concurrent therapymay be achieved by administering compositions of the disclosure and apharmaceutical composition including at least one other agent, such asan analgesic, which in combination comprise a therapeutically effectivedose, according to a particular oral dosing regimen. Administration ofthe separate pharmaceutical compositions can be performed simultaneouslyor at different times (i.e., sequentially, in either order, on the sameday, or on different days), so long as the therapeutic effect of thecombination of these substances is caused in the subject undergoingtherapy.

Compositions including a muscarinic antagonist or a pharmaceuticallyacceptable salt thereof and muscarinic agonist or a pharmaceuticallyacceptable salt thereof may be administered to the subject by anyconvenient protocol as desired or appropriate for the subject, forexample as a tablet, capsule, thin film, powder, suspension, solution,syrup, dispersion or emulsion. As described in greater detail below, thesubject compositions may contain components conventional inpharmaceutical preparations, e.g. one or more carriers, binders,lubricants, excipients (e.g., to impart controlled releasecharacteristics), pH modifiers, sweeteners, bulking agents, coloringagents or further active agents. In certain embodiments, compositionsincluding the muscarinic antagonist or a pharmaceutically acceptablesalt thereof and muscarinic agonist or a pharmaceutically acceptablesalt thereof are capsules including immediate release beads includingthe muscarinic antagonist or a pharmaceutically acceptable salt thereofand delayed-immediate release beads including the muscarinic agonist ora pharmaceutically acceptable salt thereof. For example, subjects may beorally administered a capsule containing immediate release oxybutynin ora pharmaceutically acceptable salt thereof and delayed-immediate releasepilocarpine or a pharmaceutically acceptable salt thereof.

In embodiments, subjects treated by the present methods exhibit apositive therapeutic response. By “positive therapeutic response” ismeant that the subject exhibits a reduction or elimination ofhyperhidrosis. For example, a subject exhibiting a positive therapeuticresponse to methods provided by the disclosure may exhibit responsesincluding but not limited to a reduction or elimination of axillary,palmar, plantar, craniofacial hyperhidrosis, generalized hyperhidrosis,compensatory sweating post-surgery, as reported by the subject, or asdetermined by gravimetric assessments, on the Hyperhidrosis DiseaseSeverity Scale (HDSS), by measurement by transdermal epidural watervapor loss (e.g., Vapometer, Delfin Technologies, Kuopio Finland), onthe Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa orHHVQSp), on the Hyperhidrosis Visual Analog Scale (HHVAS) or anycombination thereof.

Treatment regimens may include administering a single dose unit oradministering multiple dose units. In certain embodiments, treatmentregimens include administering multiple dose units. Unless specificallystated otherwise, “dose unit” as used herein refers to a premeasuredamount of a composition that contains a muscarinic antagonist orpharmaceutically acceptable salt thereof (e.g., oxybutynin or oxybutyninHCl) and a muscarinic agonist or pharmaceutically acceptable saltthereof (e.g., pilocarpine or pilocarpine HCl). A “single dose unit” isa single unit of a combination of a muscarinic antagonist orpharmaceutically acceptable salt thereof and a muscarinic agonist orpharmaceutically acceptable salt thereof, where the single dose unitprovides a therapeutically effective amount of the composition.“Multiple dose units” or “multiples of a dose unit” or a “multiple of adose unit” refers to at least two single dose units.

As referred to herein, a dosage interval is a single administration(e.g., orally, injection, intravenously, etc.) of a therapeuticallyeffective amount of the composition including a muscarinic antagonist ora pharmaceutically acceptable salt thereof and a muscarinic agonist or apharmaceutically acceptable salt thereof. By “multiple dosage intervals”is meant more than one dosage of the composition including themuscarinic antagonist or a pharmaceutically acceptable salt thereof andthe muscarinic agonist or a pharmaceutically acceptable salt thereof isadministered to the subject in a sequential manner. As such, the firstdosage is either removed or completely consumed by the subject and thesecond dosage is administered to the subject. In practicing methods ofthe disclosure, treatment regimens may include two or more dosingintervals, such as three or more dosing intervals, such as four or moredosing intervals, such as five or more dosing intervals, including tenor more dosing intervals. In some embodiments, the disclosed methodsinclude treating chronic hyperhidrosis by administering multiple dosesover an extended period. Alternatively or in addition, methods andcompositions of the disclosure may be administered to treat an acutecondition (e.g., hyperhidrosis caused by another drug, etc.) in singleor multiple doses for a relatively short period, for example one to twoweeks.

The duration between dosage intervals in a multiple dosage intervaltreatment regimen may vary, depending on the physiology of the subjector by the treatment regimen as determined by a health care professional.In certain instances, the duration between dosage intervals in amultiple dosage treatment regimen may be predetermined and follow atregular intervals. As such, the time between dosing intervals may varyand may be 0.5 hours or longer, such as 1 hour or longer, such as 2hours or longer, such as 4 hours or longer, such as 8 hours or longer,such as 12 hours or longer, such as 16 hours or longer, such as 24 hoursor longer, such as 48 hours or longer and including 72 hours or longer.

In other instances, the duration between dosage intervals may depend onthe response of the subject to one or more previous dosage intervals(e.g., amount of reduction in excessive sweating) as determined by ahealth care professional during the time between dosage intervals. Forexample, a subsequent dosage interval may commence if excessive sweatingdoes not decrease as desired in response to a dosage interval orincreases between dosage intervals. In yet other instances, the durationbetween dosage intervals may depend on the reduction of excessivesweating reported by the subject or as determined by gravimetricassessments, on the Hyperhidrosis Disease Severity Scale (HDSS), bymeasurement by transdermal epidural water vapor loss (e.g., Vapometer,Delfin Technologies, Kuopio Finland), on the Hyperhidrosis VisualQuantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on theHyperhidrosis Visual Analog Scale (HHVAS) or any combination thereof.

In some embodiments, methods include dosage intervals spanning multipledays. By “multiple day dosing” is meant that the muscarinic antagonistor pharmaceutically acceptable salt thereof and muscarinic agonist orpharmaceutically acceptable salt thereof are administered to the subjectover a period of time that is longer than 1 day, such as 2 days orlonger, such as 3 days or longer, such as 5 days or longer, such as 7days or longer, including 10 days or longer.

In certain embodiments, the amount of muscarinic antagonist or apharmaceutically acceptable salt thereof and muscarinic agonist or apharmaceutically acceptable salt thereof administered to the subject issufficient to achieve a particular pharmacokinetic profile. As usedherein, a “PK profile” refers to a profile of drug concentration inblood or plasma. Such a profile can be a relationship of drugconcentration over time (i.e., a “concentration-time PK profile”) or arelationship of drug concentration versus number of doses administered(i.e., a “concentration-dose PK profile”.) A PK profile is characterizedby PK parameters. As used herein, a “PK parameter” refers to a measureof drug concentration in blood or plasma, such as: 1) “drug Cmax”, themaximum concentration of drug achieved in blood or plasma; 2) “drugTmax”, the time elapsed following ingestion to achieve Cmax; and 3)“drug exposure”, the total concentration of drug present in blood orplasma over a selected period of time, which can be measured using thearea under the curve (AUC) of a time course of drug release over aselected period of time (t). Modification of one or more PK parametersprovides for a modified PK profile.

For purposes of describing the features of dose units of the presentdisclosure, “PK parameter values” that define a PK profile include drugCmax (e.g., muscarinic antagonist or muscarinic agonist Cmax), totaldrug exposure (e.g., area under the curve) (e.g., muscarinic antagonistof muscarinic agonist exposure) and 1/(drug Tmax) (such that a decreased1/Tmax is indicative of a delay in Tmax relative to a reference Tmax)(e.g., 1/muscarinic antagonist or 1/muscarinic agonist Tmax). Thus adecrease in a PK parameter value relative to a reference PK parametervalue can indicate, for example, a decrease in drug Cmax, a decrease indrug exposure, and/or a delayed Tmax.

In some embodiments, methods include administering a compositioncontaining a muscarinic antagonist or a pharmaceutically acceptable saltthereof and a muscarinic agonist or a pharmaceutically acceptable saltthereof such that peak plasma concentration of muscarinic antagonist ora pharmaceutically acceptable salt thereof and the muscarinic agonist ora pharmaceutically acceptable salt thereof are achieved at about thesame time. In other words, the composition (as described in greaterdetail below) is formulated such that maximum concentration ofmuscarinic agonist or a pharmaceutically acceptable salt thereof isachieved in the plasma at the same time as the maximum concentration ofmuscarinic antagonist or a pharmaceutically acceptable salt thereof.

In certain embodiments, dose units of the present disclosure can beadapted to provide for a modified PK profile for either the muscarinicantagonist or a pharmaceutically acceptable salt thereof or muscarinicagonist or a pharmaceutically acceptable salt thereof, e.g., a PKprofile that is different from that achieved from dosing a givenmuscarinic antagonist or a pharmaceutically acceptable salt thereof ormuscarinic agonist or a pharmaceutically acceptable salt thereof alone.For example, dose units can provide for at least one of decreased drugCmax, delayed drug Tmax and/or decreased drug exposure compared toingestion of a dose of the muscarinic antagonist or muscarinic agonistalone. Such a modification is due to the combination of muscarinicantagonist and muscarinic agonist in the dose unit.

In embodiments, a dose unit can be adapted to provide for a desired PKprofile (e.g., a concentration-time PK profile) following ingestion of asingle dose. A dose unit can be adapted to provide for a desired PKprofile (e.g., a concentration-dose PK profile) following ingestion ofmultiple dose units (e.g., at least 2, at least 3, at least 4 or moredose units).

In certain embodiments, the combination of muscarinic antagonist or apharmaceutically acceptable salt thereof and muscarinic agonist or apharmaceutically acceptable salt thereof in a dose unit can provide adesired (or “pre-selected”) PK profile (e.g., a concentration-time PKprofile) following ingestion of a single dose. The PK profile of such adose unit can be characterized by one or more of a pre-selected drugCmax, a pre-selected drug Tmax or a pre-selected drug exposure. The PKprofile of the dose unit can be modified compared to a PK profileachieved from the equivalent dosage of muscarinic antagonist ormuscarinic agonist alone.

Combinations of relative amounts of muscarinic antagonist or apharmaceutically acceptable salt thereof and muscarinic agonist or apharmaceutically acceptable salt thereof that provide for a desired PKprofile can be identified by dosing with a fixed amount of muscarinicantagonist or a pharmaceutically acceptable salt thereof and increasingamounts of muscarinic agonist or a pharmaceutically acceptable saltthereof, or with a fixed amount of muscarinic agonist or apharmaceutically acceptable salt thereof and increasing amounts ofmuscarinic antagonist or a pharmaceutically acceptable salt thereof. Oneor more PK parameters can then be assessed, e.g., drug Cmax, drug Tmax,and drug exposure. Relative amounts of muscarinic antagonist or apharmaceutically acceptable salt thereof and muscarinic agonist or apharmaceutically acceptable salt thereof that provide for a desired PKprofile are identified as amounts of muscarinic antagonist or apharmaceutically acceptable salt thereof and muscarinic agonist or apharmaceutically acceptable salt thereof for use in a dose unit. Assayscan be conducted with different relative amounts of muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof.

In vivo assays can be used to identify combinations of muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof that provide fordose units that provide for a desired concentration-dose PK profilefollowing ingestion of multiples of the dose unit (e.g., at least 2, atleast 3, at least 4 or more). Ex vivo assays can be conducted by directadministration of muscarinic antagonist or a pharmaceutically acceptablesalt thereof and muscarinic agonist or a pharmaceutically acceptablesalt thereof into a tissue and/or its contents of an animal, such as theintestine, including by introduction by injection into the lumen of aligated intestine (e.g., a gut loop, or intestinal loop, assay, or aninverted gut assay). An ex vivo assay can also be conducted by excisinga tissue and/or its contents from an animal and introducing muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof into such tissuesand/or contents.

For example, a premeasured amount of muscarinic antagonist or apharmaceutically acceptable salt thereof that is desired for a singledose unit is selected (e.g., an amount that provides an efficaciousplasma drug level). A multiple of single dose units for which arelationship between that multiple and a PK parameter to be tested isthen selected. For example, if a concentration-dose PK profile is to bedesigned for ingestion of 2, 3, 4, 5, 6, 7, 8, 9 or 10 dose units, thenthe amount of muscarinic antagonist or a pharmaceutically acceptablesalt thereof equivalent to ingestion of that same number of dose unitsis determined (referred to as the “high dose”). The multiple of doseunits can be selected based on the number of ingested pills at whichdrug Cmax is modified relative to ingestion of the single dose unit.Assays can be used to identify suitable combination(s) of muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof to obtain a singledose unit that is therapeutically effective.

Compositions for Treating Hyperhidrosis Containing a MuscarinicAntagonist and a Muscarinic Agonist or Pharmaceutically Acceptable SaltsThereof

As summarized above, aspects of the disclosure also include compositionscontaining a muscarinic antagonist or a pharmaceutically acceptable saltthereof and a muscarinic agonist or a pharmaceutically acceptable saltthereof suitable for practicing the methods described above.Compositions of interest take on any suitable form as desired orappropriate for administering to a subject in need of treatment forhyperhidrosis and may be in the form of a tablet, capsule, thin film,powder, suspension, solution, syrup, dispersion or emulsion. Thecomposition can also contain components conventional in pharmaceuticalpreparations, e.g. one or more carriers, binders, lubricants, excipients(e.g., to impart controlled release characteristics), pH modifiers,sweeteners, bulking agents, coloring agents or further active agents. Asdescribed herein, a “pharmaceutical composition” refers to thecombination of a muscarinic antagonist or a pharmaceutically acceptablesalt thereof and a muscarinic agonist or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable excipient, with whicheach of the muscarinic antagonist or a pharmaceutically acceptable saltthereof and muscarinic agonist or a pharmaceutically acceptable saltthereof are administered to a subject.

As summarized above, the subject compositions include a muscarinicantagonist or a pharmaceutically acceptable salt thereof and amuscarinic agonist or a pharmaceutically acceptable salt thereof.“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the compound. Suchsalts include: (1) acid addition salts, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the compound is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, N-methylglucamine and the like.

In certain embodiments, compositions of the invention may also includean antimicrobial agent for preventing or deterring microbial growth,such as for example benzalkonium chloride, benzethonium chloride, benzylalcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethylalcohol, phenylmercuric nitrate, thimersol, and any combinationsthereof.

One or more antioxidants may also be employed. Antioxidants, which canreduce or prevent oxidation and thus deterioration of the composition,may include, for example, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propylgallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite, and any combinations thereof.

One or more surfactants may also be included in compositions of theinvention. For example, suitable surfactants may include, but are notlimited to polysorbates, such as “Tween 20” and “Tween 80,” andpluronics such as F68 and F88 (BASF, Mount Olive, N.J.); sorbitanesters; lipids, such as phospholipids such as lecithin and otherphosphatidylcholines, phosphatidylethanolamines (although preferably notin liposomal form), fatty acids and fatty esters; steroids, such ascholesterol; chelating agents, such as EDTA; and zinc and other cations.

Acids or bases may also be present in compositions of the invention. Forexample, acids may include but are not limited to hydrochloric acid,acetic acid, phosphoric acid, citric acid, malic acid, lactic acid,formic acid, trichloroacetic acid, nitric acid, perchloric acid,phosphoric acid, sulfuric acid, fumaric acid, and any combinationsthereof. Examples of bases include, but are not limited to sodiumhydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide,ammonium acetate, potassium acetate, sodium phosphate, potassiumphosphate, sodium citrate, sodium formate, sodium sulfate, potassiumsulfate, potassium fumerate, and any combinations thereof.

The amount of any individual excipient in the oral dosage compositionwill vary depending on the nature and function of the excipient, oraldosage delivery vehicle and particular needs of the composition. In someinstances, the optimal amount of any individual excipient is determinedthrough routine experimentation, i.e., by preparing compositionscontaining varying amounts of the excipient (ranging from low to high),examining the stability and other parameters, and then determining therange at which optimal performance is attained with no significantadverse effects. Generally, however, the excipient(s) will be present inthe oral dosage composition in an amount of about 1% to about 99% byweight, such as from about 5% to about 98% by weight, such as from about15 to about 95% by weight of the excipient, including less than 30% byweight. Pharmaceutical excipients along with other excipients that maybe employed in compositions of interest are described in “Remington: TheScience & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995),the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale,N.J. (1998), and Kibbe, A. H., Handbook of Pharmaceutical Excipients,3rd Edition, American Pharmaceutical Association, Washington, D.C.,2000, the disclosure of which is herein incorporated by reference.

Where the subject compositions are oral formulations, the pharmaceuticalcomposition may include appropriate additives to make tablets, powders,granules or capsules, for example, with conventional additives, such aslactose, mannitol, corn starch or potato starch; with binders, such ascrystalline cellulose, cellulose derivatives, acacia, corn starch orgelatins; with disintegrators, such as corn starch, potato starch orsodium carboxymethylcellulose; with lubricants, such as talc ormagnesium stearate; and if desired, with diluents, buffering agents,moistening agents, preservatives and flavoring agents.

Compositions include a muscarinic antagonist or a pharmaceuticallyacceptable salt thereof. The muscarinic antagonist may be any type ofanticholinergic agent that blocks the activity of the muscarinicacetylcholine receptor, such as blockers of the M₁, M₂, M₃, M₄ or M₅muscarinic receptor isoforms. In some embodiments, the muscarinicantagonist is one or more of oxybutynin, tolterodine, 5-hydroxymethyltolterodine, fesoterodine, solifenacin, darifenaccin, tropsium,imidafenacin, propiverine or dicyclomine or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the muscarinicantagonist is oxybutynin (4-Diethylaminobut-2-ynyl2-cyclohexyl-2-hydroxy-2-phenylethanoate) or a pharmaceuticallyacceptable salt thereof.

The amount of muscarinic antagonist or pharmaceutically acceptable saltthereof in the subject compositions may vary, such as 0.5 mg or more,such as 1.5 mg or more, such as 2.5 mg or more, such as 3.0 mg or more,such as 3.5 mg or more, such as 4.0 mg or more, such as 4.5 mg or more,such as 5.0 mg or more, such as 5.5 mg or more, such as 6.0 mg or more,such as 6.5 mg or more, such as 7.0 mg or more, such as 7.5 mg or more,such as 8.0 mg or more, such as 8.5 mg or more, such as 9.0 mg or more,such as 9.5 mg or more and including 10 mg or more. For example, theamount of muscarinic antagonist in compositions of interest may rangefrom 0.5 mg to 25 mg, such as from 1 mg to 20 mg, such as from 2 mg to15 mg and including from 3 mg to 10 mg, for example 7.5 mg. In certainembodiments, the muscarinic antagonist is oxybutynin or apharmaceutically acceptable salt thereof and compositions of interestinclude 0.5 mg or more of oxybutynin or pharmaceutically acceptable saltthereof, such as 1.5 mg or more, such as 2.5 mg or more, such as 3.0 mgor more, such as 3.5 mg or more, such as 4.0 mg or more, such as 4.5 mgor more, such as 5.0 mg or more, such as 5.5 mg or more, such as 6.0 mgor more, such as 6.5 mg or more, such as 7.0 mg or more, such as 7.5 mgor more, such as 8.0 mg or more, such as 8.5 mg or more, such as 9.0 mgor more, such as 9.5 mg or more and including 10 mg or more ofoxybutynin or pharmaceutically acceptable salt thereof. For example,compositions of interest may include from 0.5 mg to 25 mg of oxybutyninor pharmaceutically acceptable salt thereof, such as from 1 mg to 20 mg,such as from 2 mg to 15 mg and including from 3 mg to 10 mg, forinstance 7.5 mg of oxybutynin or pharmaceutically acceptable saltthereof.

Compositions also include a muscarinic agonist or a pharmaceuticallyacceptable salt thereof. The muscarinic agonist may be any type of agentthat activates the activity of the muscarinic acetylcholine receptor,such as activators of the M₁, M₂, M₃, M₄ or M₅ muscarinic receptorisoforms. In some embodiments, muscarinic agonists is one or more ofpilocarpine, choline, acetylcholine, carbachol, methacholine,bethanechol, muscarine, nicotine, or oxotremorine. In certainembodiments, the muscarinic agonist is pilocarpine((3S,4R)-3-Ethyl-4-((1-methyl-1H-imidazol-5-yl)methyl)dihydrofuran-2(3H)-one).

The amount of muscarinic agonist or pharmaceutically acceptable salt inthe subject compositions may vary, such as 0.5 mg or more, such as 1.5mg or more, such as 2.5 mg or more, such as 3.0 mg or more, such as 3.5mg or more, such as 4.0 mg or more, such as 4.5 mg or more, such as 5.0mg or more, such as 5.5 mg or more, such as 6.0 mg or more, such as 6.5mg or more, such as 7.0 mg or more, such as 7.5 mg or more, such as 8.0mg or more, such as 8.5 mg or more, such as 9.0 mg or more, such as 9.5mg or more and including 10 mg or more. For example, the amount ofmuscarinic agonist in compositions of interest may range from 0.5 mg to25 mg, such as from 1 mg to 20 mg, such as from 2 mg to 15 mg andincluding from 3 mg to 10 mg, for example 7.5 mg. In certainembodiments, the muscarinic agonist is pilocarpine or pharmaceuticallyacceptable salt thereof and compositions of interest include 0.5 mg ormore of pilocarpine or pharmaceutically acceptable salt thereof, such as1.5 mg or more, such as 2.5 mg or more, such as 3.0 mg or more, such as3.5 mg or more, such as 4.0 mg or more, such as 4.5 mg or more, such as5.0 mg or more, such as 5.5 mg or more, such as 6.0 mg or more, such as6.5 mg or more, such as 7.0 mg or more, such as 7.5 mg or more, such as8.0 mg or more, such as 8.5 mg or more, such as 9.0 mg or more, such as9.5 mg or more and including 10 mg or more of pilocarpine orpharmaceutically acceptable salt thereof. For example, compositions ofinterest may include from 0.5 mg to 25 mg of pilocarpine orpharmaceutically acceptable salt thereof, such as from 1 mg to 20 mg,such as from 2 mg to 15 mg and including from 3 mg to 10 mg, forinstance 7.5 mg of pilocarpine or pharmaceutically acceptable saltthereof.

The ratio of muscarinic antagonist or a pharmaceutically acceptable saltthereof and muscarinic agonist or a pharmaceutically acceptable saltthereof in the subject compositions may vary, ranging between 1:1 and1:2.5; 1:2.5 and 1:5; 1:5 and 1:10; 1:10 and 1:25; 1:25 and 1:50; 1:50and 1:100, or a range thereof. For example, where the muscarinicantagonist is oxybutynin or a pharmaceutically acceptable salt thereofand the muscarinic agonist is pilocarpine or a pharmaceuticallyacceptable salt thereof, the mass ratio of the oxybutynin or apharmaceutically acceptable salt thereof and pilocarpine or apharmaceutically acceptable salt thereof may range from 1:1 to 1:10; orfrom 1:5 to 1:25; or from 1:10 to 1:50; or from 1:25 to 1:100. In someembodiments, the mass ratio of the muscarinic agonist orpharmaceutically acceptable salt thereof and the muscarinic antagonistor pharmaceutically acceptable salt thereof ranges between 1:1 and1:2.5; 1:2.5 and 1:5; 1:5 and 1:10; 1:10 and 1:25; 1:25 and 1:50; 1:50and 1:100, or a range thereof. For example, where the muscarinic agonistis pilocarpine or a pharmaceutically acceptable salt thereof and themuscarinic antagonist is oxybutynin or a pharmaceutically acceptablesalt thereof, the mass ratio of the pilocarpine or a pharmaceuticallyacceptable salt thereof and oxybutynin or a pharmaceutically acceptablesalt thereof may range from 1:1 to 1:10; or from 1:5 to 1:25; or from1:10 to 1:50 or from 1:25 to 1:100.

In certain embodiments, the compositions of interest are formulated asdose units, where the dosage of each of the muscarinic antagonist or apharmaceutically acceptable salt thereof and muscarinic agonist or apharmaceutically acceptable salt thereof in the dose unit ranges fromabout 0.1 mg/kg to 25 mg/kg, such as from 0.1 mg/kg to 20 mg/kg, such as0.1 mg/kg to 18 mg/kg, such as 0.1 mg/kg to 15 mg/kg, such as 0.1 mg/kgto 10 mg/kg, and including 0.1 mg/kg to 5 mg/kg. In other embodiments,the subject compositions are formulated so that each of the muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof can beadministered in a dosage of from 0.1 to 6.5 mg/kg four times per day(QID), such as 0.1 to 5 mg/kg QID, such as 0.1 mg/kg to 4 mg/kg QID. Inother embodiments, the subject compositions are formulated so that eachof the muscarinic antagonist or a pharmaceutically acceptable saltthereof and muscarinic agonist or a pharmaceutically acceptable saltthereof can be administered in a dosage of from 0.01 mg/kg to 8.5 mg/kgthree times per day (TID), such as 0.1 mg/kg to 6 mg/kg TID, such as 0.1mg/kg to 5 mg/kg TID, and including as 0.1 mg/kg to 4 mg/kg TID. In yetother embodiments the subject compositions are formulated so that eachof the muscarinic antagonist and muscarinic agonist can be administeredin a dosage of from 0.1 mg/kg to 13 mg/kg two times per day (BID), suchas 0.1 mg/kg to 12 mg/kg BID, such as 5 mg/kg to 10 mg/kg BID, including0.1 mg/kg to 8 mg/kg BID.

In certain embodiments, compositions of interest are formulated toinclude an immediate release muscarinic antagonist or pharmaceuticallyacceptable salt thereof and a delayed onset immediate release muscarinicagonist or a pharmaceutically acceptable salt thereof. For example, thesubject compositions may include an immediate release oxybutynin or apharmaceutically acceptable salt thereof and a delayed-immediate releasepilocarpine or a pharmaceutically acceptable salt thereof. The termsimmediate release and delayed onset immediate release are used herein intheir conventional sense to refer to the timing that the muscarinicantagonist or a pharmaceutically acceptable salt thereof and muscarinicagonist or a pharmaceutically acceptable salt thereof, respectively, arereleased after administration.

In some embodiments, the immediate release muscarinic antagonist or apharmaceutically acceptable salt thereof (e.g., oxybutynin or oxybutyninHCl) is formulated to release 50% or more of the muscarinic antagonistor a pharmaceutically acceptable salt thereof within 10 minutes or lessof administration of the composition to the subject, such as 60% ormore, such as 75% or more, such as 90% or more, such as 95% or more andincluding 99% or more within 10 minutes or less of administration of thecomposition to the subject. In certain instances, the immediate releasemuscarinic antagonist or a pharmaceutically acceptable salt thereof(e.g., oxybutynin or oxybutynin HCl) is formulated to release 50% ormore of the muscarinic antagonist or a pharmaceutically acceptable saltthereof immediately after administration of the composition to thesubject, such as 60% or more, such as 75% or more, such as 90% or more,such as 95% or more and including 99% or more immediately afteradministration of the composition to the subject.

In embodiments, the immediate release muscarinic antagonist may beformulated as a powder, microparticle or as a granulate. The muscarinicantagonist may include a polymer, such as cellulose, microcrystallinecellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, maltodextrin,sucrose, modified starch, a salt of alginic acid, soluble gums,carrageenan, polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone(PVPP), ethylcellulose, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, insoluble gums,polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetatephthalate or a combination thereof. In certain embodiments, themuscarinic antagonist component is a granulate of oxybutynin or apharmaceutically acceptable salt thereof that includes microcrystallinecellulose and polyvinylpyrrolidone.

In other embodiments, the muscarinic antagonist component may furtherinclude a lipid excipient, such as glyceryl behenate, glycerol esters offatty acids, glyceryl dibehenate, behenoyl macrogoglycerides, glyceryldistearate, glycerol distearate, glyceryl palmitostearate, lauroylmacrogoglycerides, stearoyl macrogoglycerides, abitec products, glycerylmono-oleate, medium chain mono- & diglycerides, glyceryl monocaprylate,glyceryl tricaprylate/caprate/stearate, hydrogenated vegetable oil,hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenatedsoybean oil and castor wax, polyoxyethylene 8 caprylic/capricglycerides, polyoxyethylene 6 caprylic/capric glycerides,polyoxyethylene 32 lauric glycerides, polyoxyethylene 6 prop. glycolesters, polyoxyethylene 7 coconut glycerides, polyoxyethylene 30 coconutglycerides, polyoxyethylene 80 coconut glycerides, polyoxypropylene 15stearyl ether, polyoxyethylene 26 glyceryl ether, polyoxyethylene 35soybean glycerides, polyoxyethylene 20 sorbitol, polyoxypropylene 3myristyl ether, polyoxypropylene 10 cetostearyl ether, palm kernelamidediethanolamide, triglycerol mono-oleate, sasol products, hydrogenatedcoco-glycerides, cetyl palmitate, trimyristin, tripalmitin, tristearin,hydrogenated palm oil, glyceryl monostearate, glyceryl stearate,cetearyl alcohol, cetyl alcohol, capric triglyceride, acetylatedglycerides, glyceryl cocoate, and polyethylene glycol.

In other embodiments, the muscarinic antagonist component may furtherinclude a de-tackifier or glidant, such as talc, a monoglyceride, adiglyceride, glyceryl monostearate, calcium stearate, and magnesiumstearate.

In still other embodiments, the immediate release muscarinic antagonistis formulated as beads including a core with muscarinic antagonist or apharmaceutically acceptable salt thereof (e.g., oxybutynin or oxybutyninHCl) layered on top of the core. In some embodiments, the core comprisesbetween about 10% to about 90% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises betweenabout 25% to about 85% of the total weight of the finally-formulatedbead. In some embodiments, the core comprises between about 40% to about80% of the total weight of the finally-formulated bead. In someembodiments, the core comprises about 80% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises about75% of the total weight of the finally-formulated bead. In someembodiments, the core comprises about 85% of the total weight of thefinally-formulated bead.

In some embodiments, a solution of the muscarinic antagonist or apharmaceutically acceptable salt thereof, is prepared and then sprayedonto the core and then dried. The act of spraying and drying causes alayer of the muscarinic antagonist or a pharmaceutically acceptable saltthereof to form over the bead. In some embodiments, the solutioncomprises a polymer that causes the muscarinic antagonist or apharmaceutically acceptable salt thereof to more efficiently adhere tothe core. The amount of the muscarinic antagonist or a pharmaceuticallyacceptable salt thereof present in the dosage form can be controlled bycontrolling the thickness of the layer. The thicker the layer the moremuscarinic antagonist or a pharmaceutically acceptable salt thereof ispresent in the dosage form. Once the layer of muscarinic antagonist or apharmaceutically acceptable salt thereof is exposed to aqueous media(e.g., gastric or intestinal juice), the muscarinic antagonist or apharmaceutically acceptable salt thereof immediately dissolves into theaqueous medium.

In some embodiments, the layer of muscarinic antagonist or apharmaceutically acceptable salt thereof comprises between about 1% toabout 50% of the total weight of the bead. In some embodiments, thelayer of muscarinic antagonist or a pharmaceutically acceptable saltthereof comprises between about 2% to about 40% of the total weight ofthe bead. In some embodiments, the layer of muscarinic antagonist or apharmaceutically acceptable salt thereof comprises between about 4% toabout 25% of the total weight of the bead. In some embodiments, layer ofmuscarinic antagonist or a pharmaceutically acceptable salt thereofcomprises between about 5% to about 15% of the total weight of the bead.In some embodiments, the layer of muscarinic antagonist or apharmaceutically acceptable salt thereof comprises between about 5.5% toabout 10% of the total weight of the bead. In some embodiments, thelayer of muscarinic antagonist or a pharmaceutically acceptable saltthereof comprises about 6% of the total weight of the bead. In someembodiments, the layer of muscarinic antagonist or a pharmaceuticallyacceptable salt thereof comprises about 6.5% of the total weight of thebead. In some embodiments, the layer of muscarinic antagonist or apharmaceutically acceptable salt thereof comprises about 7% of the totalweight of the bead. In some embodiments, the layer of muscarinicantagonist or a pharmaceutically acceptable salt thereof comprises about8% of the total weight of the bead.

The muscarinic antagonist or a pharmaceutically acceptable salt thereofmay be layered onto the core with a film-forming polymer, such ascellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, maltodextrin,sucrose, modified starch, a salt of alginic acid, soluble gums,carrageenan, polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone(PVPP), ethylcellulose, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, insoluble gums,polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetatephthalate.

The layer of muscarinic antagonist or a pharmaceutically acceptable saltthereof may also contain a lipid excipient, a detackifier and a glidant,as described above.

In some embodiments, the delayed onset immediate release muscarinicagonist or a pharmaceutically acceptable salt thereof (e.g., pilocarpineor pilocarpine HCl) is formulated such that 20% or less of themuscarinic agonist or a pharmaceutically acceptable salt thereof (e.g.,pilocarpine or pilocarpine HCl) in the composition is releasedapproximately 20 minutes after administration to the subject and 75% ormore of the muscarinic agonist or a pharmaceutically acceptable saltthereof in the composition is released approximately 30 minutesthereafter. In these embodiments, 20% or less of the muscarinic agonistor a pharmaceutically acceptable salt thereof (e.g., pilocarpine orpilocarpine HCl) in the composition is released approximately 20 minutesafter administration to the subject, such as 15% or less, such as 10% orless, such as 5% or less, such as 3% or less and including 1% or less ofthe muscarinic agonist or a pharmaceutically acceptable salt thereof(e.g., pilocarpine or pilocarpine HCl) is released approximately 20minutes after administration to the subject. After 20 minutes, thedelayed onset immediate release muscarinic agonist or a pharmaceuticallyacceptable salt thereof is formulated to release 75% or more of themuscarinic agonist or a pharmaceutically acceptable salt thereofapproximately 30 minutes thereafter, such as 80% or more, such as 85% ormore, such as 90% or more, such as 95% or more, such as 97% or more andincluding 99% or more. In certain embodiments, 20 minutes afteradministration, the composition is formulated to release 100% of themuscarinic agonist approximately 30 minutes thereafter.

In certain embodiments, the delayed onset immediate release muscarinicagonist or pharmaceutically acceptable salt thereof is formulated torelease the muscarinic agonist according to a release profile asgenerally depicted in FIG. 2.

In certain embodiments, the delayed onset immediate release muscarinicagonist or a pharmaceutically acceptable salt thereof is formulated asbeads including a core with a first layer of muscarinic agonist or apharmaceutically acceptable salt thereof (e.g., pilocarpine orpilocarpine HCl) coated on top of the core and a second layer includingat least one polymer coated on top of the muscarinic agonist or apharmaceutically acceptable salt thereof-containing layer.

In these embodiments, the core may include, but is not limited to, sugarbeads (for example, Paular spheres), microcrystalline cellulose,Cellets® cores, such as Cellets® 100, Cellets® 200, Cellets® 350,Cellets® 500, Cellets® 700, or Cellets® 1000 (Glatt Air Techniques Inc.,Ramsey N.J.). In other embodiments, the core is prepared de novo, forexample by preparing a polymer mixture, extruding the mixture, andspheronizing the extruded mixture to form spherical or semi-sphericalbeads. In some embodiments, the beads are swellable such that theirexposure to aqueous media causes them to swell and release the activeingredient rapidly and efficiently. In some embodiments, the corecomprises between about 10% to about 50% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises betweenabout 15% to about 40% of the total weight of the finally-formulatedbead. In some embodiments, the core comprises between about 20% to about30% of the total weight of the finally-formulated bead. In someembodiments, the core comprises about 20% of the total weight of thefinally-formulated bead. In some embodiments, the core comprises about25% of the total weight of the finally-formulated bead. In certainembodiments, the core includes a Cellets 700 microcrystalline cellulosebead.

In some embodiments, a first layer including a muscarinic agonist or apharmaceutically acceptable salt thereof (e.g., pilocarpine orpilocarpine HCl) is formed on the core. In some embodiments, the firstlayer comprises between about 1% to about 50% of the total weight of thebead. In some embodiments, the first layer comprises between about 2% toabout 40% of the total weight of the bead. In some embodiments, thefirst layer comprises between about 5% to about 30% of the total weightof the bead. In some embodiments, the first layer comprises betweenabout 7% to about 25% of the total weight of the bead. In someembodiments, the first layer comprises between about 8% to about 15% ofthe total weight of the bead. In some embodiments, the first layercomprises about 8% of the total weight of the bead. In some embodiments,the first layer comprises about 10% of the total weight of the bead. Insome embodiments, the first layer comprises about 12% of the totalweight of the bead. In some embodiments, the first layer comprises about15% of the total weight of the bead.

In certain embodiments, the first layer containing the muscarinicagonist or a pharmaceutically acceptable salt thereof further includes apolymer such as cellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, maltodextrin, sucrose, modified starch, a saltof alginic acid, soluble gums, carrageenan, polyvinylpyrrolidone (PVP)or polyvinylpolypyrrolidone (PVPP), ethylcellulose, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, insoluble gums,polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetatephthalate and combinations thereof.

In some embodiments, the first layer containing the muscarinic agonistor a pharmaceutically acceptable salt thereof may further include ade-tackifier or glidant, such as talc, a monoglyceride, a diglyceride,glyceryl monostearate, calcium stearate, and magnesium stearate.

In other embodiments, the first layer containing the muscarinic agonistor a pharmaceutically acceptable salt thereof includes a lipidexcipient, such as glyceryl behenate, glycerol esters of fatty acids,glyceryl dibehenate, behenoyl macrogoglycerides, glyceryl distearate,glycerol distearate, glyceryl palmitostearate, lauroylmacrogoglycerides, stearoyl macrogoglycerides, abitec products, glycerylmono-oleate, medium chain mono- & diglycerides, glyceryl monocaprylate,glyceryl tricaprylate/caprate/stearate, hydrogenated vegetable oil,hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenatedsoybean oil and castor wax, polyoxyethylene 8 caprylic/capricglycerides, polyoxyethylene 6 caprylic/capric glycerides,polyoxyethylene 32 lauric glycerides, polyoxyethylene 6 prop. Glycolesters, polyoxyethylene 7 coconut glycerides, polyoxyethylene 30 coconutglycerides, polyoxyethylene 80 coconut glycerides, polyoxypropylene 15stearyl ether, polyoxyethylene 26 glyceryl ether, polyoxyethylene 35soybean glycerides, polyoxyethylene 20 sorbitol, polyoxypropylenemyristyl ether, polyoxypropylene 10 cetostearyl ether, palm kernelamidediethanolamide, triglycerol mono-oleate, sasol products, hydrogenatedcoco-glycerides, cetyl palmitate, trimyristin, tripalmitin, tristearin,hydrogenated palm oil, glyceryl monostearate, glyceryl stearate,cetearyl alcohol, cetyl alcohol, capric triglyceride, acetylatedglycerides, glyceryl cocoate, and polyethylene glycol or combinationsthereof.

In certain embodiments, the first layer containing the muscarinicagonist or a pharmaceutically acceptable salt thereof includespilocarpine or a pharmaceutically acceptable salt thereof, hydroxypropylmethylcellulose and talc.

In some embodiments, delayed onset immediate release formulations ofmuscarinic agonists or pharmaceutically acceptable salts thereof includea polymer layer (second layer) formed on top of the muscarinic agonistor a pharmaceutically acceptable salt thereof layer. Suitable polymersmay include, but are not limited to, cellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, maltodextrin, sucrose, modified starch, a saltof alginic acid, soluble gums, carrageenan, polyvinylpyrrolidone (PVP)or polyvinylpolypyrrolidone (PVPP), ethylcellulose, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, insoluble gums,polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetatephthalate and combinations thereof. In some embodiments, the secondlayer comprises between about 1% to about 50% of the total weight of thebead. In some embodiments, the second layer comprises between about 2%to about 40% of the total weight of the bead. In some embodiments, thesecond layer comprises between about 5% to about 30% of the total weightof the bead. In some embodiments, the second layer comprises betweenabout 7% to about 25% of the total weight of the bead. In someembodiments, the second layer comprises between about 8% to about 15% ofthe total weight of the bead. In some embodiments, the second layercomprises about 8% of the total weight of the bead. In some embodiments,the second layer comprises about 10% of the total weight of the bead. Insome embodiments, the second layer comprises about 12% of the totalweight of the bead. In some embodiments, the second layer comprisesabout 15% of the total weight of the bead.

In certain embodiments, the polymer layer coated on the muscarinicagonist or a pharmaceutically acceptable salt thereof layer includesethylcellulose and hydroxypropylcellulose. The ratio ofhydroxypropylcellulose to ethylcellulose may range between about 5:1 toabout 1:5 by weight. In some embodiments, the ratio ofhydroxypropylcellulose to ethylcellulose is between about 4:1 to about1:4 by weight. In some embodiments, the ratio of hydroxypropylcelluloseto ethylcellulose is between about 3:1 to about 1:3 by weight. In someembodiments, the ratio of hydroxypropylcellulose to ethylcellulose isbetween about 2:1 to about 1:2 by weight. In other embodiments, theratio of ethylcellulose to hydroxypropylcellulose may range betweenabout 5:1 to about 1:5 by weight. In some embodiments, the ratio ofethylcellulose to hydroxypropylcellulose is between about 4:1 to about1:4 by weight. In some embodiments, the ratio of ethylcellulose tohydroxypropylcellulose is between about 3:1 to about 1:3 by weight. Insome embodiments, the ratio of ethylcellulose to hydroxypropylcelluloseis between about 2:1 to about 1:2 by weight. In some embodiments, theratio of hydroxypropylcellulose to ethylcellulose is about 1:1 byweight.

In some embodiments, the polymer layer coated on the muscarinic agonistor a pharmaceutically acceptable salt thereof layer includes aplasticizer, such as a phthalate-based plasticizer, a trimellitate, anadipate-based plasticizer, a sebacate-based plasticizer, anorganophosphate, a maleate, a sulfonamide, a glycols or polyether, anacetylated monoglyceride, and an alkyl citrate. The plasticizer may bepresent in between about 1% to about 50% of the total weight of thebead. In some embodiments, the plasticizer is present in between about2% to about 40% of the total weight of the bead. In some embodiments,the plasticizer is present in between about 3% to about 20% of the totalweight of the bead. In some embodiments, the plasticizer is present inbetween about 4% to about 10% of the total weight of the bead. In someembodiments, the plasticizer is present in about 4% of the total weightof the bead. In some embodiments, the plasticizer is present in about4.5% of the total weight of the bead. In some embodiments, theplasticizer is present in about 5% of the total weight of the bead. Insome embodiments, the plasticizer is present in about 5.5% of the totalweight of the bead. In some embodiments, the plasticizer is present inabout 6% of the total weight of the bead. In some embodiments, theplasticizer is present in about 6.5% of the total weight of the bead.

For example, the phthalate-based plasticizer may be bis(2-ethylhexyl)phthalate (DEHP), diisononyl phthalate (DINP), bis(n-butyl)phthalate(DnBP, DBP), butyl benzyl phthalate (BBzP), diisodecyl phthalate (DIDP),di-n-octyl phthalate (DOP or DnOP), diisooctyl phthalate (DIOP), diethylphthalate (DEP), diisobutyl phthalate (DIBP), and di-n-hexyl phthalate.In some embodiments, the trimellitate is selected from the groupconsisting of trimethyl trimellitate (TMTM), tri-(2-ethylhexyl)trimellitate (TEHTM-MG), tri-(n-octyl,n-decyl) trimellitate (ATM),tri-(heptyl,nonyl) trimellitate (LTM), and n-octyl trimellitate (OTM).In some embodiments, the adipate-based plasticizer is selected from thegroup consisting of bis(2-ethylhexyl)adipate (DEHA), dimethyl adipate(DMAD), monomethyl adipate (MMAD), and dioctyl adipate (DOA). In someembodiments, the sebacate-based plasticiser is dibutyl sebacate (DBS).In some embodiments, the maleate is dibutyl maleate (DBM) or diisobutylmaleate (DIBM). In some embodiments, the sulfonamide is selected fromthe group consisting of ortho or para N-ethyl toluene sulfonamide(ETSA), N-(2-hydroxypropyl)benzene sulfonamide (HP BSA), andN-(n-butyl)benzene sulfonamide (BBSA-NBBS). In some embodiments, theorganophosphate is tricresyl phosphate (TCP) or tributyl phosphate(TBP). In some embodiments, the glycol or polyether is selected from thegroup consisting of triethylene glycol dihexanoate (3G6, 3 GH),tetraethylene glycol diheptanoate (4G7), and polyethylene glycol. Insome embodiments, the alkyl citrate is selected from the groupconsisting of Triethyl citrate (TEC), acetyl triethyl citrate (ATEC),tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate(TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC, trihexylo-butyryl citrate), and trimethyl citrate (TMC). In some embodiments,the plasticizer is selected from the group consisting of dibutylsebacate, polyethylene glycol, glycerin, triacetin, diethyl phthalate,propylene glycol, triethyl citrate, mineral oil, an acetylatedmonoglyceride, and oleic acid. In certain embodiments, the layer on topof the muscarinic agonist layer includes dibutyl sebacate.

In some embodiments, the weight of the second layer is between about 50%to about 300% of the weight of the bead prior to the application of thesecond layer. In some embodiments, the weight of the second layer isbetween about 75% to about 250% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 75% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 100% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 125% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 150% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 175% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 200% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 225% of the weight of the bead prior to theapplication of the second layer. In some embodiments, the weight of thesecond layer is about 250% of the weight of the bead prior to theapplication of the second layer.

In certain embodiments, the muscarinic agonist or a pharmaceuticallyacceptable salt thereof component of the subject compositions includesbeads including:

a microcrystalline core;

a first layer coated on the microcrystalline core containing pilocarpineor a pharmaceutically acceptable salt thereof, hydroxypropylmethylcellulose and talc; and

a second layer coated on the first layer containing ethylcellulose,hydroxypropylcellulose and dibuty sebacate.

In certain embodiments, the muscarinic agonist or a pharmaceuticallyacceptable salt thereof component of the subject compositions includesbeads including:

a microcrystalline core that is about 20% of the total weight of thebead

a first layer on top of the microcrystalline core containing pilocarpineor a pharmaceutically acceptable salt thereof present in an amount thatis about 8% of the total weight of the bead, hydroxypropylmethylcellulose present in an amount that is about 8% of the totalweight of the bead and talc present in an amount that is about 4% of thetotal weight of the bead; and

a second layer coated on the first layer containing ethylcellulosepresent in an amount that is about 26% of the total weight of the bead,hydroxypropylcellulose present in an amount that is about 26% of thetotal weight of the bead, and dibutyl sebacate present in an amount thatis about 5% of the total weight of the bead.

In certain embodiments, the subject compositions containing a muscarinicantagonist or a pharmaceutically acceptable salt thereof and amuscarinic agonist or a pharmaceutically acceptable salt thereof arethose described in United States Patent Publication No. 2011/0244051filed on Apr. 1, 2011, the disclosure of which is herein incorporated byreference in its entirety.

In certain embodiments, the muscarinic agonist or pharmaceuticallyacceptable salt thereof is formulated as a mini-tablet including a corecomprising the muscarinic agonist or pharmaceutically acceptable saltthereof and a coating layer that includes a coating polymer.

In some embodiments, the core comprises between about 70% to about 99%of the total weight of the finally-formulated mini-tablet. In someembodiments, the core comprises between about 75% to about 97% of thetotal weight of the finally-formulated mini-tablet. In some embodiments,the core comprises between about 80% to about 95% of the total weight ofthe finally-formulated mini-tablet. In some embodiments, the corecomprises between about 85% to about 95% of the total weight of thefinally-formulated mini-tablet. In some embodiments, the core comprisesbetween about 88% to about 95% of the total weight of thefinally-formulated mini-tablet.

In some embodiments, a stock solution comprising the muscarinic agonist(e.g., pilocarpine) or a pharmaceutically acceptable salt thereof, and apolymer is prepared and then sprayed onto a fluidized bed, usingmethodology well-known in the art. In some embodiments, the fluidizedbed is a cellulose bed. In some of these embodiments, the fluidized bedis a microcrystalline cellulose bed. In further embodiments, thefluidized bed is a silicified microcrystalline cellulose bed. In someembodiments, the fluidized bed is, for example, PROSOLV® SMCC, such asPROSOLV® SMCC 50.

In some embodiments, the core further includes an osmotic agent. Theosmotic agent in certain instances causes the core to disintegraterapidly and release the API as soon as the core comes into contact withan aqueous medium, such as the gastric or intestinal juice. In someembodiments, the osmotic agent is an inorganic salt. In some of theseembodiments, the salt is a salt of an alkali metal. In furtherembodiments, the salt is a halide slat of an alkali metal. In someembodiments, the salt is selected from the group consisting of lithiumchloride, lithium bromide, lithium iodide, sodium chloride, sodiumbromide, sodium iodide, potassium chloride, potassium bromide, andpotassium iodide.

In some embodiments, the core comprises a disintegrant. In someembodiments, the disintegrant is a cross-linked polymer. In some ofthese embodiments, the cross-linked polymer is cross-linkedpolyvinylpyrrolidone (crospovidone) or cross-linked sodium carboxymethylcellulose (croscarmellose sodium). In other embodiments, thedisintegrant is a modified starch, for example sodium starch glycolate.

In some embodiments, the core further includes a lubricant. In someembodiments, the lubricant is a mineral, such as talc or silica. Inother embodiments, the lubricant is a fat, e.g., vegetable stearin,magnesium stearate, stearic acid, or a derivatized stearic acid. In someembodiments, the derivatized stearic acid is sodium stearyl fumarate.

In some embodiments, the muscarinic agonist or pharmaceuticallyacceptable salt thereof (e.g., pilocarpine or pharmaceuticallyacceptable salt thereof) is present in the core between about 0.1% toabout 5% by weight of the core. In other embodiments, the muscarinicagonist or pharmaceutically acceptable salt thereof is present in thecore between about 0.3% to about 4% by weight; or between about 0.5% toabout 3% by weight.

In some embodiments, the fluidized bed, i.e., cellulose, in the core ispresent in between about 40% to about 75% by weight of the core, orbetween about 45% to about 70% by weight, or between about 48% to about65% by weight of the core.

In some embodiments, the core polymer is present in between about 4% toabout 15% by weight of the core, or between about 5% to about 12% byweight, or between about 5% to about 10% by weight of the core.

In some embodiments, the disintegrant is present in between about 5% toabout 35% by weight of the core, or between about 5% to about 25% byweight, or between about 10% to about 30% by weight, or between about10% to about 20% by weight, or between about 12% to about 17% by weightof the core.

In some embodiments, the salt is present in between about 10% to about50% by weight of the core, or between about 10% to about 40% by weight,or between about 12% to about 37% by weight, or between about 15% toabout 35% by weight of the core.

In some embodiments, the lubricant is present in between about 0.2% toabout 2% by weight of the core, or between about 0.5% to about 1.7% byweight, or between about 0.5% to about 1.5% by weight of the core.

In mini-tablets of interest, the core is coated by a coating layer. Incertain embodiments, the coating layer is formulated to delay theexposure of the core to aqueous media, for example gastric juice orintestinal fluid. The coating layer includes a coating polymer. Incertain embodiments, the coating polymer is a cellulose polymer. In someof these embodiments, the cellulose polymer is microcrystallinecellulose. In other embodiments, the coating polymer is a derivatizedcellulose, for example, alkylated cellulose. In some of theseembodiments, the derivatized cellulose is selected from the groupconsisting of ethyl cellulose, propyl cellulose and hydroxylpropylcellulose.

In some embodiments, the application of the coating layer causes aweight gain of between about 1% to about 50% of the weight of themini-tablet prior to the application of the coating layer. Thus, forexample, if the weight of the core prior to the application of thecoating layer is X, then after the application of the coating layer, theweight of the mini-tablet is 1.01×, if the weight gain is 1%, or theweight of the mini-tablet is 1.5×, if the weight gain is 50%. In someembodiments, the weight gain is between about 5% to about 45%. In someembodiments, the weight gain is between about 5% to about 40%. In someembodiments, the weight gain is between about 5% to about 35%. In someembodiments, the weight gain is between about 5% to about 30%. In someembodiments, the weight gain is between about 10% to about 25%.

In some embodiments, the coating polymer includes a sugar or apolysaccharide. In some of these embodiments, the sugar orpolysaccharide is selected from the group consisting of cellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, maltodextrin,sucrose, modified starch, a salt of alginic acid, soluble gums, andcarageenan. In other embodiments, the coating polymer comprisespolyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone (PVPP).

In some embodiments, the coating polymer is a mixture of two or morepolymers. In some embodiments, the mixture comprises ethylcellulose (EC)and hydroxypropylcellulose (HPC). In certain instances, EC is present inbetween about 60% to about 95% of the weight of the coating, or betweenabout 60% to about 85% of the weight, or between about 61% to about 84%by weight, or between about 61% to about 82% by weight. In certaininstances, HPC is present in between about 5% to about 35% of the weightof the coating, or between about 5% to about 20% of the weight, orbetween about 7% to about 17% by weight, or between about 7% to about16% by weight.

In some embodiments, the coating further includes a lubricant. In someembodiments, the lubricant is a mineral, such as talc or silica. In someembodiments, the lubricant is present in between about 1% to about 20%of the weight of the coating, or between about 5% to about 17% byweight, or between about 10% to about 16% by weight.

In some embodiments, the coating further includes a plasticizer. In someembodiments, the plasticizer is selected from the group consisting of aphthalate-based plasticizer, a trimellitate, an adipate-basedplasticizer, a sebacate-based plasticizer, an organophosphate, amaleate, a sulfonamide, a glycols or polyether, an acetylatedmonoglyceride, and an alkyl citrate. In some embodiments, thesebacate-based plasticiser is dibutyl sebacate (DBS). In someembodiments, the plasticizer is present in between about 1% to about 20%of the weight of the coating, or between about 5% to about 15% byweight, or between about 7% to about 10% by weight.

In certain embodiments, the subject mini-tablets containing a muscarinicagonist or a pharmaceutically acceptable salt thereof (e.g., pilocarpineor pharmaceutically acceptable salt thereof) are those described inUnited States Patent Publication No. 2014/0105976 filed on Oct. 11,2013, the disclosure of which is herein incorporated by reference in itsentirety.

Aspects, including embodiments, of the subject matter described hereinmay be beneficial alone or in combination, with one or more otheraspects or embodiments. Without limiting the description, certainnon-limiting aspects of the disclosure numbered 1-34 are provided below.As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individually numbered aspects may be used orcombined with any of the preceding or following individually numberedaspects. This is intended to provide support for all such combinationsof aspects and is not limited to combinations of aspects explicitlyprovided below:

-   -   1. A method of treating hyperhidrosis with a muscarinic        antagonist and reducing a dry mouth side effect of the        muscarinic antagonist in a subject in need thereof, the method        comprising:        -   administering to the subject a therapeutically effective            amount of a composition comprising a muscarinic antagonist            or a pharmaceutically acceptable salt thereof and a            muscarinic agonist or a pharmaceutically acceptable salt            thereof,        -   wherein the administering is effective at reducing            hyperhidrosis, and        -   wherein the administering is sufficient to reduce a dry            mouth side effect of the muscarinic antagonist.    -   2. The method according to 1, wherein the subject is diagnosed        as having primary focal axillary hyperhidrosis.    -   3. The method according to 1, wherein the subject is diagnosed        as having primary focal palmar hyperhidrosis.    -   4. The method according to 1, wherein the subject is diagnosed        as having plantar hyperhidrosis.    -   5. The method according to 1, wherein the subject is diagnosed        as having craniofacial hyperhidrosis.    -   6. The method according to 1, wherein the subject is diagnosed        as having generalized hyperhidrosis.    -   The method according to 1, wherein the subject is diagnosed as        having compensatory sweating post-surgery.    -   8. The method according to any one of 1-7, wherein the        muscarinic antagonist is oxybutynin or a pharmaceutically        acceptable salt thereof.    -   9. The method according to any one of 1-8, wherein the        muscarinic agonist is pilocarpine or a pharmaceutically        acceptable salt thereof.    -   10. The method according to 8 or 9, wherein the composition        comprises from about 5 to about 30 mg of oxybutynin or a        pharmaceutically acceptable salt thereof.    -   11. The method according to 10, wherein the composition        comprises about 7.5 mg of oxybutynin or a pharmaceutically        acceptable salt thereof.    -   12. The method according to 11, wherein the composition        comprises about 5.0 mg of oxybutynin or a pharmaceutically        acceptable salt thereof.    -   13. The method according to any one of 9-12, wherein the        composition comprises from about 5 to about 30 mg of pilocarpine        or a pharmaceutically acceptable salt thereof.    -   14. The method according to claim 13, wherein the composition        comprises about 7.5 mg of pilocarpine or a pharmaceutically        acceptable salt thereof.    -   15. The method according to 13, wherein the composition        comprises about 5.0 mg of pilocarpine or a pharmaceutically        acceptable salt thereof.    -   16. The method according to any one of 1-15, wherein the method        comprises administering the composition once per day.    -   17. The method according to any one of 1-15, wherein the method        comprises administering the composition twice per day.    -   18. The method according to any one of 1-15, wherein the method        comprises administering the composition for one month or longer.    -   19. The method according to any one of 1-15, wherein the method        comprises administering the composition for one year or longer.    -   20. The method according to any one of 8-19, wherein the        composition comprises an immediate release composition        comprising oxybutynin or a pharmaceutically acceptable salt        thereof and a delayed onset immediate release composition        comprising pilocarpine or a pharmaceutically acceptable salt        thereof.    -   21. The method according to any one of 8-20, wherein the        composition is formulated such that the peak plasma        concentration of oxybutynin or a pharmaceutically acceptable        salt thereof and the peak plasma concentration of pilocarpine or        a pharmaceutically acceptable salt thereof in the subject occurs        at approximately the same time.    -   22. The method according to 21, wherein the delayed onset        immediate release composition is formulated such that less than        20% of the pilocarpine or a pharmaceutically acceptable salt        thereof in the composition is released approximately 20 minutes        after administration to the subject and 90% or more of the        pilocarpine or a pharmaceutically acceptable salt thereof in the        composition is released approximately 30 minutes thereafter.    -   23. The method according to 21, wherein the composition        comprises:        -   oxybutynin or a pharmaceutically acceptable salt thereof;            and        -   a plurality of pilocarpine beads, each pilocarpine bead            comprising:            -   a core;        -   a first layer positioned over the core comprising            pilocarpine or a pharmaceutically acceptable salt thereof;            and            -   a second layer positioned over the first layer                comprising hydroxypropylcellulose and ethylcellulose.    -   24. The method according to 21, wherein the composition        comprises:        -   oxybutynin or a pharmaceutically acceptable salt thereof;            and        -   a plurality of pilocarpine mini-tablets, each pilocarpine            mini-tablet comprising:            -   a core comprising pilocarpine; and            -   a coating layer comprising a coating polymer.    -   25. The method according to 24, wherein the coating layer        comprises a sugar or a polysaccharide selected from the group        consisting of cellulose, ethylcellulose (EC),        hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),        hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose,        maltodextrin, sucrose, modified starch, a salt of alginic acid,        soluble gums, carageenan, and a combination thereof.    -   26. The method according to 24, wherein the coating layer        comprises polyvinylpyrrolidone (PVP) or polyvinylpolypyrrolidone        (PVPP).    -   27. The method according to any one of 1-26, wherein dry mouth        is reduced as determined by a dry mouth visual analog scale.    -   28. The method according to any one of 1-27 wherein dry mouth is        reduced as reported by the subject with a dry mouth        incidence/severity questionnaire.    -   29. The method according to any one of 1-28 wherein        hyperhidrosis is reduced as measured on the hyperhidrosis        disease severity scale.    -   30. The method according to any one of 1-29, wherein        hyperhidrosis is reduced as measured by axillary, plantar or        palmar gravimetric analysis.    -   31. The method according to any one of 1-30, wherein        hyperhidrosis is reduced as measured by a hyperhidrosis visual        quantification scale.    -   32. The method according to any one of 1-31, wherein        hyperhidrosis is reduced as measured by a hyperhidrosis visual        analog scale.    -   33. The method according to any one of 1-32, wherein        hyperhidrosis is reduced as measured by transdermal epidural        water vapor loss.    -   34. A method of treating hyperhidrosis with oxybutynin or a        pharmaceutically acceptable salt thereof and reducing a dry        mouth side effect of the oxybutynin with pilocarpine or a        pharmaceutically acceptable salt thereof in a subject in need        thereof, the method comprising:        -   administering to the subject a therapeutically effective            amount of a composition comprising 5 to 30 mg of oxybutynin            or a pharmaceutically acceptable salt thereof and 5 to 30 mg            pilocarpine or a pharmaceutically acceptable salt thereof,        -   wherein the composition is formulated such that the peak            plasma concentration of oxybutynin or a pharmaceutically            acceptable salt thereof and the peak plasma concentration of            pilocarpine or a pharmaceutically acceptable salt thereof in            the subject occurs at approximately the same time,        -   wherein the administering is at least as effective at            reducing hyperhidrosis in the subject as administration of            oxybutynin or a pharmaceutically acceptable salt thereof            alone, and    -   wherein the administering is sufficient to reduce a dry mouth        side effect of the oxybutynin or a pharmaceutically acceptable        salt thereof.

The following examples are offered by way of illustration and not by wayof limitation. Specifically, the following examples are of specificembodiments for carrying out the present disclosure. The examples arefor illustrative purposes only, and are not intended to limit the scopeof the present disclosure in any way. Efforts have been made to ensureaccuracy with respect to numbers used (e.g., amounts, temperatures,etc.), but some experimental error and deviation should, of course, beallowed for.

EXPERIMENTAL Preparation of Example Muscarinic Antagonist and MuscarinicAgonist Formulations

Capsules containing a muscarinic antagonist component and a muscarinicagonist component were prepared. The muscarinic antagonist(oxybutynin—as oxybutynin HCl) was prepared as a granulate and themuscarinic agonist (pilocarpine—as pilocarpine HCl) was prepared asmultilayer beads. Capsules containing 7.5 mg of oxybutynin HCl granulateand 7.5 mg of pilocarpine HCl multilayer beads were prepared asdescribed below.

Active Agents

Oxybutynin HCl is a white crystalline powder. Pilocarpine HCl is a whiteto almost white crystalline powder.

Materials

Table 1 lists the compounds used in the preparing capsules containing amuscarinic antagonist component and a muscarinic agonist component.

TABLE 1 Generic Name Trade Name Oxybutynin HCl — Pilocarpine HCl —Povidone K-29/32 Plasdone K29/32 Silicified Microcrystalline CelluloseProsolv SMCC 50 Microcrystalline Cellulose Beads Cellets 700Hydroxypropyl Methylcellulose Pharmacoat 606 (HPMC) Talc Pharma 400Ethylcellulose Aqualon EC-N10 Hydroxypropyl Cellulose Klucel EXF DibutylSebacate — 200 Proof Ethanol — White Opaque Gelatin Capsules, Size 0Coni-Snap Sterile water —

Pilocarpine Beads

Inert microcrystalline cellulose beads were coated with two layers: adrug layer containing immediate release pilocarpine HCl, and a delayedrelease polymer layer. The overall formulation for the pilocarpinedelayed onset immediate release beads is summarized in Table 2. FIG. 1illustrates the process for manufacturing the pilocarpine beads with thecomponents listed in Table 2. Tables 3-4 provides process parameters forpreparing the pilocarpine beads.

TABLE 2 Component Chemical Name Description % w/w mg/dose CoreMicrocrystalline Coating 20.8 18.75 cellulose pellets substrateMuscarinic Agonist Pilocarpine HCl Active Agent 8.3 7.5 MuscarinicAgonist Hydroxypropyl Film former 8.3 7.5 Layer MethylcelluloseMuscarinic Agonist Talc De-tackifier 4.2 3.75 Layer Release LayerHydroxylpropyl Film Former 26.5 23.83 Cellulose Release LayerEthylcellulose Film Former 26.5 23.83 Release Layer Dibutyl SebacatePlasticizer 5.3 4.77

TABLE 3 Fluid Bead Pilocarpine Layering Equipment Vector FLM1 Batch size0.70 kg Process air 45-50 CFM Spray rate 12-17 g/min. Atmospheric AirPressure 37 psi Inlet Temperature 82 ± 5° C. Product Temperature 50 ± 2°C. Dew Point 10° C.

TABLE 4 Fluid Bead Release Polymer Layering Equipment Vector FLM1 Batchsize 0.53 kg Process air 58-60 CFM Spray rate 22-30 g/min. AtmosphericAir Pressure 40 psi Inlet Temperature 52 ± 5° C. Product Temperature 35± 2° C. Dew Point 8° C.

The pilocarpine beads prepared were tested for dissolution in 0.1 N HClto and provide a delayed onset immediate release profile forpilocarpine. FIG. 2 depicts the dissolution profile of beads preparedaccording to Table 2.

Oxybutynin Granulate

A high shear oxybutynin HCl granulation was prepared. The overallformulation for the oxybutynin HCl immediate release granulate issummarized in Table 5. FIG. 3 illustrates the process for manufacturingthe oxybutynin granulate with the components listed in Table 5. Table 6provides process parameters for preparing the oxybutynin granulate.

TABLE 5 Component Chemical Name Description % w/w mg/dose MuscarinicOxybutynin HCl Active Agent 18.75 7.5 Antagonist PolymerPolyvinylpyrrolidone Binder 3.75 1.5 Polymer Silicified Binder 77.5031.0 microcrystalline cellulose

TABLE 6 High Shear Granulation Equipment Vector GMX 4L Batch size 0.90kg Process air 58-60 CFM Muscarinic Antagonist/Binder Solution WaterImpeller Speed 547 rpm Chopper Speed 1800 rpm Tray Drying Temperature50° C. Drying Time 8 hours Final LOD % 1.91% Milling Equipment QuadroComil 197S Batch size 0.89 kg Screen 24R Impeller Square Impeller speed3000 rpm

The oxybutynin granulate was hand filled into size 0 gelatin capsuleswhich were tested for dissolution in 0.1 N HCl to and provided animmediate release profile for oxybutynin. FIG. 4 depicts the dissolutionprofile of the oxybutynin granulate prepared according to Table 5.

Compositions for Treating Hyperhidrosis with Oxybutynin and Pilocarpine

The coated pilocarpine HCl beads and oxybutynin HCl granulate describedabove were encapsulated into size 0 gelatin capsules. Table 7 summarizesthe formulation prepared for treating hyperhidrosis.

TABLE 7 Component % w/w mg/dose Oxybutynin HCl Granulate 17.7 40.0Pilocarpine HCl Beads 39.8 89.9 Size 0 white gelatin capsule 4.25 96.0

Each capsule was partially filled with the oxybutynin HCl granulateusing a Xcelodose 120S semi-automatic encapsulator. Capsules werepartially filled in groups of 10 by the Xcelodose. 89.9 mg ofpilocarpine HCl beads were weighed and manually filled into eachcapsule. A cap was manually placed onto each capsule and each capsulewas manually closed. THVD-102 [7.5/7.5] is a composition as prepared inthis example for treating subjects with hyperhidrosis (as described ingreater detail below) that contains 7.5 mg of oxybutynin HCl and 7.5 mgof pilocarpine HCl.

Treatment of Hyperhidrosis with a Therapeutically Effective Amount of aComposition Including a Muscarinic Antagonist and Muscarinic Agonist

Clinical Study Objectives

One objective of the study includes evaluating the safety and efficacyof THVD-102 [7.5/7.5] (a composition including oxybutynin andpilocarpine as prepared above) in subjects with primary focalhyperhidrosis (e.g., axillary and/or palmar). Another objective of thestudy includes evaluating dry mouth and quality of life in subjectsreceiving THVD-102 [7.5/7.5] (oxybutynin plus pilocarpine).

Clinical Study Design

The clinical study was a randomized, double blind, placebo-controlled,crossover study of approximately 18 subjects. Following qualification,subjects were randomized to one of 6 groups/sequences during which theyreceived each of the three study treatments in sequential treatmentperiods. Each 21-day double-blind study treatment period was preceded byan at least 7-day washout period. Subsequent study treatment assignmentswere via the sequential three-way crossover design prescribed in thatgroup. After completing the final study treatment period or early studytreatment discontinuation, all subjects completed an end of study visit(approximately 14 days after the last study treatment administration.FIG. 5 illustrates a scheme of the clinical study design.

As described above, this was a cross-over design study in which allsubjects were to receive all 3 of the study treatments (1 in each of the3 double-blind treatment periods). The use of the crossover designallowed a smaller number of subjects and introduced lower variability aseach subject acted as his/her own control.

The study was preceded by an Oxybutynin Run-in Period during whichsubjects received oxybutynin 5 mg twice daily by mouth; this wasincorporated to help identify subjects who had anti-muscarinic induceddry mouth that could be measured using the Dry Mouth Visual Analog Scale(DMVAS). A minimum score of 25 mm on a 100 mm scale was required on theDMVAS.

Placebo was used as the comparator for safety and the comparator forefficacy in hyperhidrosis; THVD-102 [7.5/7.5] and oxybutynin were bothcompared to placebo.

The active control of oxybutynin 7.5 mg is the comparator for THVD-102[7.5/7.5] for the anti-muscarinic induced dry mouth symptom incidenceand severity.

Subjects were randomized to 1 of 6 groups/sequences of study treatmentadministration. Each sequence included sequential crossover assignmentto a 21-day treatment period of:

-   -   oxybutynin 7.5 mg BID alone by mouth;    -   THVD-102 [7.5/7.5] (oxybutynin 7.5 mg in combination with        pilocarpine 7.5 mg) BID by mouth; and    -   placebo BID by mouth.

To be included in the clinical study, subjects must have met alleligibility criteria, including a Hyperhidrosis Disease Severity Scale(HDSS) score of 3 or 4 on Day 1 of Treatment Period 1 and a DMVAS scoreof at least 25 mm following the run-in period of open-label oxybutynin.Initially, 3 to 4 subjects were randomized to each group/sequence for atotal of 21 to ensure at least 18 completed subjects. Subjects who donot complete all 3 three double-blind treatment periods were replaced.

Following qualification, subjects were randomized to one of 6groups/sequences during which they were to receive each of the 3 studytreatments in sequential 21-day double-blind treatment periods. Eachdouble-blind treatment period was preceded by a washout period of atleast 7 days.

Subsequent study treatment assignments were assigned according to thesequential three-way cross-over design prescribed for the group to whichthe subject was assigned. The study treatment assignments are summarizedin Table 8.

TABLE 8 Study Treatment Assignment Treatment Treatment Treatment GroupPeriod 1 Period 2 Period 3 1 A B C 2 A C B 3 B A C 4 B C A 5 C A B 6 C BA Total 18 18 18

Subjects were randomized and enrolled following confirmation ofeligibility. All subjects received the same dose of THVD-102 [7.5/7.5]and oxybutynin. Subjects were instructed to take the study treatment atapproximately the same times of day (e.g. 7:00 am and 7:00 pm). Allstudy visits were conducted at approximately the same time of day toavoid diurnal variation in study assessments and to allow at least 4hours from the time of study treatment administration on that morning,if applicable. Subjects were instructed to take the morning dose ofstudy treatment as scheduled prior to Day 21 assessments. If a subjectmissed a planned study drug administration, it was to be taken anytimeduring that calendar day; subjects were instructed not to administerstudy treatment more than 2 times each calendar day and not within 6hours of the previous administration. The 12-hour interval between studydrug administrations was intended to provide a close to 24-hour periodof coverage and consistent dose intensity.

Study drug compliance was assessed at each visit when unused study drugwas returned. The amount of study drug returned was compared with theamount of study drug dispensed and that was expected to have beenadministered. Subjects with inadequate study drug compliance (<80%) mayhave been discontinued from study treatment.

Subjects returned to the investigational site for safety and efficacyassessments at the end of each treatment period (Day 21); subsequenttreatment periods began at least 7 days following the end of thepreceding period to allow a sufficient washout period.

At the conclusion of all 3 treatment periods (or in the case of earlystudy treatment discontinuation), subjects returned to theinvestigational site for safety assessments approximately 14 daysfollowing the last study treatment administration for follow-up (End ofStudy Visit).

Study assessments for efficacy/activity included:

-   -   Hyperhidrosis Disease Severity Scale (HDSS)    -   Gravimetric assessments (axillary [paper] &/or palmar        [paper+glove])    -   Rate of water vapor loss using a closed chamber device; Delfin        VapoMeter    -   Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa        or HHVQSp) for axillary and/or palmar    -   Hyperhidrosis Visual Analog Scale (HHVAS)    -   Dry Mouth Visual Analog Scale (DMVAS)    -   Dermatology-specific HRQOL as assessed by a modified Dermatology        Life Quality Index    -   Dry Mouth Questions (Dry Mouth Severity/Incidence Questionnaire)    -   Transepidermal Water Vapor Loss (axillary and palmar)—Vapometer,        Delfin Technologies, Kuopio Finland

Study assessments were conducted at baseline (Day 1 of each treatmentperiod), at the end of treatment (Day 21 of each treatment period), andat the End of Study (EOS) Visit (approximately at least 14 daysfollowing the last study drug administration). Subjects who completedthe study treatment period between Days 21 and 28 were instructed tocontinue taking study treatment as prescribed until the “Day 21 Visit”.

Dry mouth was not recorded as adverse events but only via the DMVAS andthe dry mouth questions (Dry Mouth Severity/Incidence Questionnaire).

Subjects who discontinued study treatment early were asked to completethe EOS Visit approximately 14 days after the last study treatmentadministration. Subjects were monitored for safety and concomitantmedication use at all visits.

Efficacy Measurements

Hyperhidrosis Disease Severity Scale (HDSS)

The HHDS is a tool for the assessment of disease severity in patientswith

PFH (Lowe, 2004; Strutton, 2004; Solish, 2005; Kowalski, 2006).

The HDSS is a self-administered assessment in which the subject is askedto rate the severity of his/her hyperhidrosis by responding to thequestion “How would you rate the severity of your hyperhidrosis?” Thescale has 4 scores from which to select

-   -   1. My sweating is never noticeable and never interferes with my        daily activities    -   2. My sweating is tolerable but sometimes interferes with my        daily activities    -   3. My sweating is barely tolerable and frequently interferes        with my daily activities    -   4. My sweating is intolerable and always interferes with my        daily activities

These assessments were obtained as baseline (the beginning of eachtreatment period and at the end for each treatment period).

Hyperhidrosis Visual Quantification Scale (HHVQS)

Subjects with axillary hyperhidrosis were asked to complete theHyperhidrosis Visual Quantification Scale for Axillary (HHVQSa) andsubjects with palmar hyperhidrosis were asked to complete HyperhidrosisVisual Quantification Scale for Palmer (HHVQSp). Subject with bothaxillary and palmar hyperhidrosis were to complete both assessments.These assessments were obtained as baseline (the beginning of eachtreatment period and at the end for each treatment period.

Axillary (HHVQSa)

Subjects were asked to quantify their axillary hyperhidrosis byresponding to 2 directions:

-   -   1. Choose the picture that best described your worst experience        over the past week.    -   2. Choose the picture that best describes your most common        experience over the past week.

Beneath each request, there were 4 descriptive diagrams of an axillawith the following captions:

-   -   1. Normal    -   2. Moist    -   3. Wet    -   4. Dripping

FIG. 6 depicts the axillary Hyperhidrosis Visual Quantification Scale(HHVQSa).

Palmar (HHVQSp)

Subjects were asked to quantify their palmar hyperhidrosis by respondingto 2 directions:

-   -   1. Choose the picture that best described your worst experience        over the past week.    -   2. Choose the picture that best describes your most common        experience over the past week.

Beneath each request, there were 4 descriptive diagrams of a pair ofhands with the following captions:

-   -   1. Normal Hands    -   2. Moist hands    -   3. Wet hands    -   4. Dripping hands

FIG. 7 depicts the palmar Hyperhidrosis Visual Quantification Scale(HHVQSp).

Hyperhidrosis Visual Analog Scale (HHVAS)

The HHVAS was used to quantify the severity of sweating in subjectsduring this clinical trial. Subjects will be instructed to indicatetheir level of disease severity by drawing a line through the continuousscale. The continuous scale was 100 mm in length. The score wasdetermined by measuring the distance from the left anchor to where theline that the subject drew bisected the (100 mm) scale. The distance wasmeasured and recorded in millimeters (mm). FIG. 8 depicts theHyperhidrosis Visual Analog Scale used to assess sweating.

Dry Mouth Visual Analog Scale (DMVAS)

The DMVAS will be used to quantify the severity of dry mouth experiencedby subjects during this clinical trial. Subjects will be instructed toindicate their level of disease severity by drawing a line through thecontinuous scale. The score was determined by measuring the distancefrom the left anchor to where the line that the subject drew bisectedthe (100 mm) scale. The distance was measured and recorded inmillimeters (mm). FIG. 9 depicts the Dry Mouth Visual Analog Scale usedto assess dry mouth cause by administration of oxybutynin.

Dry Mouth Questions (Dry Mouth Severity/Incidence Questionnaire)

At the end of the end of each treatment period, investigational sitestaff questioned subjects regarding the incidence of dry mouth. Thisassessment occurred after the subject had completed the DMVAS and DTVASand included questions relating to the incidence and severity of drymouth symptoms and remedial actions taken. The investigator wasinstructed to query subjects in a non-judgmental, non-leading mannerusing the following script (© 2012, Thomas Tremblay and Robin Allgren)to elicit the incidence of dry mouth:

-   -   Have you had any dry mouth since starting (the most recent)        study treatment? (at completion of Treatment Periods 1, 2, and        3)        If the subject indicated that dry mouth had occurred, the        investigator was to qualify the dry mouth using the following        script.    -   Which term: “mild”, “moderate”, or “severe” best describes the        dry mouth you experienced?    -   Did you drink additional fluids to relieve your dry mouth?    -   Did you need to use hard candy or other types of lozenges to        relieve your dry mouth?    -   Did you use any other types of products to moisten your mouth or        relieve dryness?    -   On a scale of 0 to 10, with “0” being “not severe at all” and        “10” being “the most severe imaginable”, how would you rate the        worst dry mouth that you experienced?

Gravimetric Testing

Gravimetric testing was used to quantify the amount of sweat produced bysubjects prior to and following each study treatment.

Axillary Gravimetric Testing

Subjects with axillary hyperhidrosis were asked to refrain fromapplication of topical antiperspirants and topical deodorants to theunderarm region (bilateral) for the 24 hours prior to gravimetrictesting. The evening prior to gravimetric testing, subjects were toshave the underarms and cleanse the areas thoroughly using a mild soap(e.g.; castile soap) to ensure that any residual deodorant orantiperspirant agent was removed.

If a subject had used antiperspirant within the 24 hours prior toplanned axillary gravimetric testing, gravimetric testing was notperformed and the subject was be re-instructed and rescheduled. Subjectsin whom gravimetric testing was delayed continued to receive study drugper protocol until the rescheduled testing is completed.

If a subject neglected to shave and cleanse the underarms the eveningbefore planned axillary gravimetric testing but did abstain fromantiperspirant the underarms were shaved and cleaned prior togravimetric testing and gravimetric testing was performed as scheduled.

Prior to gravimetric testing the axillary areas were completely driedusing an absorbent non-lint producing fabric (e.g.; gauze sponge).Following drying of the axillae, a 4×6 inch absorbent cotton gauze pad(or equivalent) and the bag in which it is packaged was be weighed andthe gauze was removed from the bag, folded in half and placed high inthe axillary vaults and the subject was instructed to rest for 5 minuteswith his/her arm(s) adducted to the torso with normal tension.

At the completion of 5 minutes, the gauze was to be removed, placed backin the same bag and weighed immediately. The difference in the weight ofthe gauze prior to the test and following the test was recorded.

Palmar Gravimetric Testing

Prior to gravimetric testing, subjects washed their hands using a mildsoap and thoroughly dry the hands using an absorbent non-lint producingfabric (e.g.; gauze sponge or paper towels). Following drying of thehands, a pre-weighed cotton glove was placed on each of the hands of thesubject and the cotton gloves were covered by pre-weighed nitrilegloves. The gloves were taped tightly around their wrists to preventwater loss. The subject was instructed to rest for 5 minutes withhis/her hands in the gloves and down at their sides (to prevent waterloss).

At the completion of 5 minutes, the cotton and nitrile gloves wereremoved and weighed immediately. The difference in the weight of thegloves prior to the test and following the test was recorded.

Transepidermal Water Vapor Loss

The Delfin VapoMeter (Delfin Technologies Ltd., Kuopio, Finland), aportable device that can measure water vapor loss through the skin, wasused to evaluate the results of treating primary hyperhidrosis. It is aportable non-invasive instrument that has a closed measurement chamberthat eliminates any interference from drafts (air conditioning andbreathing, as well as the opening and closing of doors and windows),allowing accurate measurement of transepidermal water loss. The chambercontains relative humidity and temperature sensors.

To standardize the quantification of sweating, all subjects remained atrest for 20-30 minutes before the measurements in order to reduceexternal interference. The measurements were carried out in atemperature-controlled environment (21-24° C.).

For the measurements, the device was positioned perpendicular to theskin, remaining in contact with the skin surface until signaling thatthe reading was finished (generally 10 seconds). The evaporation ratewas automatically calculated by the device on the basis of an increasein relative humidity in the closed chamber. This measurement expressesthe increase in water mass (in g) in relation to the area of evaporation(in m²) per unit of time (in h), the unit of measurement being thereforeg/m2/h.

Axillary Transepidermal Water Vapor Loss

The device was placed perpendicular to the axillary skin at the top ofthe crease/fold and the arm will be closed. Transepidermal water lossassessments was conducted prior to gravimetric testing and on bothaxilla.

Palmar Transepidermal Water Vapor Loss

Measurements were carried out on the hypothenar region on both hands.

Modified Dermatology Life Quality Index (mDLQI)

The DLQI (Finlay, Kahn 1994) is a self administered assessment used toquantify the health-related quality of life of adults suffering from askin disease and consists of 10 questions concerning the perception ofthe impact of skin diseases on different aspects of their health relatedquality of life over the last week. It has been validated for adulthyperhidrosis patients aged 16 years and older (Swartling 2001). Forthis study, the DLQI was modified to replace “skin” with “sweating” inthe instructions and questionnaire items.

Clinical Study Population

Potential subjects were identified by outreach to local dermatologistswho could refer their patients, by advertisement, and by a social mediacampaign. Subjects contacted the study center and were preliminarilyscreened via telephone interview and, if possibly eligible, were thenevaluated in person. As mentioned above, potential subjects needed todemonstrate measurable anti-muscarinic induced dry mouth symptoms usingthe DMVAS. The study group included men and women age 18 to 70 withprimary focal hyperhidrosis.

Subjects were included into the study based on the below inclusioncriteria:1. Able to provide written/signed informed consent.2. Age 18 to 70 years old at time of informed consent.3. Confirmed diagnosis of primary focal palmar and/or axillaryhyperhidrosis.4. Adequate renal and hepatic function defined as:

a. Serum creatinine and estimated creatinine clearance <1.5×upper limitof normal range, and

b. ALT or AST <1.5×upper limit of normal.

5. Negative serum pregnancy test for women of child bearing potentialwithin the 7 days prior to the first study drug administration andwilling to use an effective method of contraception for the duration ofthe clinical trial.6. Willingness and ability to comply with the study protocol for theduration of the trial.7. HDSS score of 3 or 4 at Visit 1.8. A rating of ‘wet hands’ or “dripping hands” on the HyperhidrosisVisual Quantification Scale (HHVQS) at Visit 1 for subjects with palmarhyperhidrosis.9. Dry Mouth/Throat Visual Analog Scale (DM/TVAS) score of >25 mm atVisit 2.10. A rating of “wet hands” or “dripping hands” on the HyperhidrosisVisual Quantification Scale palmar (HHVQSp) for subjects with palmarhyperhidrosis or “wet” or “dripping” on the Hyperhidrosis VisualQuantification Scale axillary (HHVQSa) at Oxybutynin Run in Period Day−1 or Day −1 of Treatment Period 1 if they completed the OxybutyninRun-In as a part of Study THVD 402 20111. Dry Mouth Visual Analog Scale (DMVAS) score of 25 mm at OxybutyninRun in Period Day 21. Subjects who participated in Study THVD 402 201who have a documented DMVAS of at least 25 mm following the OxybutyninRun-In period do not need to complete the open label oxybutynin run inperiod in this trial; these subjects can begin this trial with TreatmentPeriod 1.Subjects were excluded from the study based on the below exclusioncriteria:1. Contraindication to oxybutynin and/or pilocarpine including:

a. Urinary retention or significant bladder outflow obstruction

b. Gastric retention, gastrointestinal obstructive disorder (e.g.,pyloric stenosis), or decreased gastric motility

c. Narrow-angle glaucoma or acute iritis

d. Myasthenia gravis

e. Asthma, chronic bronchitis or COPD requiring pharmacological therapy

f. Significant cardiovascular disease, including uncontrolledhypertension

g. Known or suspected cholelithiasis or biliary tract disease

h. Known or suspected renal colic or nephrolithiasis

i. Previous hypersensitivity to pilocarpine or oxybutynin.

j. Any other condition in which administration of oxybutynin orpilocarpine may pose a significant risk to the patient

2. Botox (onabotulinumtoxinA) treatment during the 8 months prior toscreening or iontophoresis during the 2 months prior to screening.3. History of local surgical excision of eccrine or apocrine glands ofthe axillae.4. Any reason, in the opinion of the investigator that a subject wouldnot be a reliable subject and provide accurate data.

All subjects will be warned against prolonged exposure to heat and/orsunshine.

Statistics

Efficacy and safety analyses were conducted on study treatment (THVD-102[7.5/7.5], oxybutynin or placebo). Continuous data were summarized byusing descriptive statistics (mean, SD, median, min, max) andcategorical data were summarized in frequency tables. Using Day 1 of thefirst and each subsequent Treatment Period as baselines for measuringtreatment effect, a Wilcoxon signed-rank test were performed. Safetyanalyses were performed in terms of the incidence and severity ofadverse events. A p value of ≤0.05 was considered statisticallysignificant. Primary comparisons of oxybutynin alone and THVD-102[7.5/7.5] were made compared to placebo and each other in the followingparameters:

-   -   Hyperhidrosis Disease Severity Scale (HDSS)    -   Gravimetric measurements (axillary and/or palmar)    -   Rate of water vapor loss using a closed chamber device    -   Hyperhidrosis Visual Quantification Scale (HHVQS)    -   Hyperhidrosis Visual Analog Scale (HHVAS)    -   Dry Mouth Visual Analog Scale (DMVAS)    -   Dry Mouth Questions (Dry Mouth Severity/Incidence Questionnaire)    -   Dermatology-specific HRQOL as assessed by a modified Dermatology        Life Quality Index    -   Vital signs        Overall Conclusions from Clinical Study    -   THVD-102 [7.5/7.5] was generally well tolerated. No unexpected        adverse effects were observed. The incidence and type of        anti-muscarinic adverse effects was no greater than that which        has been observed in prior trials of oxybutynin. There was no        occurrence of a muscarinic adverse effect in the trial.    -   THVD-102 [7.5/7.5] was efficacious in the treatment of primary        focal hyperhidrosis. There was a statistically significant        effect in each of three measures of efficacy:        -   1) Hyperhidrosis Disease Severity Scale (p=0.03-0.05)            THVD-102 [7.5/7.5]=1.06±1.11; Oxybutynin=1.33±1.03;            placebo=0.5±0.62    -   1 point drop=50% reduction in sweating; 2 points=80% reduction        -   2) Hyperhidrosis Visual Analog Scale (p=0.01)        -   3) Hyperhidrosis Visual Quantification Scale (p=0.005-0.07)    -   The efficacy of THVD-102 [7.5/7.5] was not significantly        different than that of oxybutynin in any of the categories.    -   Table 9 summarizes efficacy measurements by the above three        measures.

TABLE 9 Measurements & p Values HHVQSa HHVQSa HHVQSp HHVQSp HDSS HDSSHHVAS PP (most PP PP (most PP PP IT PP common) (worst) common) (worst) n18 23 16 17 17 6 7 THVD-102 <0.05 0.03 0.002 0.005 0.007 0.07 0.04[7.5/7.5] v. placebo THVD-102 0.45 0.78 0.8 0.40 0.45 0.31 0.31[7.5/7.5] v. Oxybutynin

-   -   THVD-102 [7.5/7.5] and oxybutynin resulted in a significant        improvement in the quality of life (mDLQI) versus placebo        (p<0.02 and p<0.04, respectively). The improvement in quality of        life was not significantly different than that shown with        oxybutynin (p=0.72). FIG. 10 depicts the improvement in quality        of life by THVD-102 [7.5/7.5] as compared to placebo.    -   Using two different measurements, THVD-102 [7.5/7.5] showed a        statistically significant reduction in dry mouth compared to        oxybutynin. A significant reduction was shown in severity of dry        mouth, using the Dry Mouth Visual Analog Scale (Table 10), and        in the incidence of moderate to severe dry mouth using a        questionnaire (Table 11). Incidence of none or mild vs. moderate        or severe (THVD-102 [7.5/7.5] vs. oxybutynin p=0.02). Dry mouth        visual analog scale (THVD-102 [7.5/7.5] vs. oxybutynin p=0.05)

TABLE 10 Dry mouth Visual Analog Scale, 100 mm scale, 100 = worst (PP)Comparison of change in VAS Scores THVD-102 Placebo Oxybutynin [7.5/7.5]n 18 18 18 Change D0-D21 5.6 ± 26.7 43.9 ± 27.9 29.9 ± 31.0 ActualReduction −14.0 (p < 0.049) % Reduction 32%

TABLE 11 Questionnaire tool-incidence (PP) None/mild vs moderate/severedry mouth THVD-102 Placebo Oxybutynin [7.5/7.5] n 18 18 18 None/Mild 16(88%)  5 (27%) 10 (56%) Moderate/Severe  2 (11%) 13 (72%)  8 (44%)Oxybutynin v. Placebo p < 0.0001 THVD-102 [7.5/7.5] v. Placebo p = 0.04THVD-102 [7.5/7.5] v. p = 0.02 Oxybutynin

Although the foregoing disclosure has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this disclosure that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

Accordingly, the preceding merely illustrates the principles of thedisclosure. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the disclosure andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the disclosure and theconcepts contributed by the inventors to furthering the art, and are tobe construed as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the disclosure as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentdisclosure, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent disclosure is embodied by the appended claims.

1.-30. (canceled)
 31. A method of treating hyperhidrosis in a subject inneed thereof, the method comprising: orally administering to the subjectonce per day or twice per day a single unit dose of a therapeuticallyeffective amount of a composition comprising an immediate releaseformulation of about 1 mg to 10 mg of oxybutynin, or a pharmaceuticallyacceptable salt thereof, and a delayed-immediate release formulation ofabout 1 mg to 10 mg of pilocarpine, or a pharmaceutically acceptablesalt thereof.
 32. The method according to claim 31, wherein thedelayed-immediate release formulation of pilocarpine, or apharmaceutically acceptable salt thereof, comprises a plurality ofdelayed-immediate release pilocarpine beads, wherein each pilocarpinebead comprises: a core; a first layer comprising pilocarpine, or apharmaceutically acceptable salt thereof, positioned over the core; anda second layer comprising at least one polymer positioned over the firstlayer.
 33. The method according to claim 31, wherein the composition isadministered once per day.
 34. The method according to claim 31, whereinthe subject is diagnosed as having one or more condition selected fromthe group consisting of primary focal axillary hyperhidrosis, primaryfocal palmar hyperhidrosis, primary focal plantar hyperhidrosis,craniofacial hyperhidrosis, generalized hyperhidrosis, and compensatorysweating post-surgery.
 35. The method according to claim 31, wherein thecomposition administered contains about 4 mg of the oxybutynin, orpharmaceutically acceptable salt thereof, and pilocarpine, or apharmaceutically acceptable salt thereof, in an amount selected from thegroup consisting of about 4 mg, about 6 mg, and about 9 mg.
 36. Themethod according to claim 31, wherein the composition administeredcontains about 6 mg of the oxybutynin, or pharmaceutically acceptablesalt thereof, and pilocarpine, or a pharmaceutically acceptable saltthereof, in an amount selected from the group consisting of about 4 mg,about 6 mg, and about 9 mg.
 37. The method according to claim 31,wherein the composition administered contains about 9 mg of theoxybutynin, or pharmaceutically acceptable salt thereof, andpilocarpine, or a pharmaceutically acceptable salt thereof, in an amountselected from the group consisting of about 4 mg, about 6 mg, and about9 mg.
 38. The method according to claim 31, wherein the compositioncomprises oxybutynin hydrochloride (HCl) and pilocarpine hydrochloride(HCl).
 39. The method according to claim 31, wherein the composition isformulated such that the peak plasma concentration of the oxybutynin, ora pharmaceutically acceptable salt thereof, and the peak plasmaconcentration of the pilocarpine, or a pharmaceutically acceptable saltthereof, occurs at approximately the same time.
 40. The method accordingto claim 32, wherein the first layer comprises a polymer selected fromthe group consisting of cellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, maltodextrin, sucrose, modified starch, a saltof alginic acid, soluble gums, carrageenan, polyvinylpyrrolidone (PVP)or polyvinylpolypyrrolidone (PVPP), ethylcellulose, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, insoluble gums,polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetatephthalate.
 41. The method according to claim 40, wherein the first layercomprises hydroxypropylmethylcellulose.
 42. The method according toclaim 32, wherein the second layer comprises one or more polymersselected from the group consisting of cellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, maltodextrin, sucrose, modified starch, a saltof alginic acid, soluble gums, carrageenan, polyvinylpyrrolidone (PVP)or polyvinylpolypyrrolidone (PVPP), ethylcellulose, cellulose acetatephthalate, hydroxypropylmethylcellulose phthalate, insoluble gums,polymethacrylate, a polyvinyl alcohol, shellac, and polyvinyl acetatephthalate.
 43. The method according to claim 42, wherein the secondlayer comprises ethylcellulose and hydroxypropylcellulose.
 44. Themethod according to claim 43, wherein the ratio ofhydroxypropylcellulose to ethylcellulose is from about 5:1 to about 1:5by weight.
 45. The method according to claim 44, wherein the ratio ofhydroxypropylcellulose to ethylcellulose is about 1:1 by weight.
 46. Themethod according to claim 32, wherein the core is about 15% to about 40%of the total weight of the bead, the first layer is about 5% to about30% of the total weight of the bead, and the second layer is about 40%to about 70% of the total weight of the bead.
 47. The method accordingto claim 32, wherein the core is a microcrystalline core that is about20% of the total weight of the bead; the first layer comprises thepilocarpine, or a pharmaceutically acceptable salt thereof, in an amountthat is about 8% of the total weight of the bead, hydroxypropylmethylcellulose in an amount that is about 8% of the total weight of thebead, and talc in an amount that is about 4% of the total weight of thebead; and the second layer comprises ethylcellulose in an amount that isabout 26% of the total weight of the bead, hydroxypropylcellulose in anamount that is about 26% of the total weight of the bead, and dibutylsebacate in an amount that is about 5% of the total weight of the bead.48. The method according to claim 32, wherein the plurality ofdelayed-immediate release pilocarpine beads are formulated such that 20%or less of pilocarpine, or a pharmaceutically acceptable salt thereof,is released approximately 20 minutes after administering to the subject,and about 75% or more of pilocarpine, or a pharmaceutically acceptablesalt thereof, is released approximately 30 minutes thereafter.